L. Payne, M. Arneborn, A. Tegnell, and J. Giesecke, Endemic tularemia, Infect. Dis, vol.11, pp.1440-1442, 1017.

J. L. Pérez-castrillón, P. Bachiller-luque, M. Martín-luquero, F. J. Mena-martín, and V. Herreros, , 2001.

, Tularemia Epidemic in Northwestern Spain: Clinical Description and Therapeutic Response, Infect. Dis, vol.33, pp.573-576, 1020.

J. M. Petersen, J. K. Carlson, G. Dietrich, R. J. Eisen, J. Coombs et al., Multiple 1022 Francisella tularensis Subspecies and Clades, Tularemia Outbreak, Utah. Emerg. Infect. Dis, vol.14, pp.1928-1023, 1930.

T. Piercy, J. Steward, M. S. Lever, and T. J. Brooks, In vivo efficacy of fluoroquinolones against 1025 systemic tularaemia infection in mice, J. Antimicrob. Chemother, vol.56, pp.1069-1073, 1026.

P. Pilo, A. Johansson, and J. Frey, Identification of Francisella tularensis Cluster in Central and 1028 Western Europe, Emerg. Infect. Dis, vol.15, pp.2049-2051, 2009.

C. R. Raymond and J. W. Conlan, Differential susceptibility of Sprague-Dawley and Fischer 344 rats 1030 to infection by Francisella tularensis, Microb. Pathog, vol.46, pp.231-234, 1031.

R. Reintjes, I. Dedushaj, A. Gjini, T. R. Jorgensen, B. Cotter et al., Tularemia outbreak 1033 investigation in Kosovo: case control and environmental studies, Emerg. Infect. Dis, vol.8, pp.69-73, 2002.

R. Lyons, C. Wu, and T. H. , Animal models of Francisella tularensis infection, Ann. N. Y. Acad. Sci, vol.1035, issue.1105, pp.238-265, 2007.

S. Rockwood, Tularemia: What's in a name, ASM News, pp.63-65, 1983.

S. Rotem, E. Bar-haim, H. Cohen, U. Elia, R. Ber et al., Consequences of Delayed 1038 Ciprofloxacin and Doxycycline Treatment Regimens against Francisella tularensis Airway Infection, 2012.

, Antimicrob. Agents Chemother, vol.56, pp.5406-5408

P. Russell, S. M. Eley, M. J. Fulop, D. L. Bell, and R. W. Titball, The efficacy of ciprofloxacin and 1041 doxycycline against experimental tularaemia, J. Antimicrob. Chemother, vol.41, pp.461-465, 1042.

O. Scheel, T. Hoel, T. Sandvik, and B. P. Berdal, Susceptibility pattern of Scandinavian Francisella 1044 tularensis isolates with regard to oral and parenteral antimicrobial agents, APMIS, vol.101, pp.33-36, 1045.

D. M. Schmitt, D. M. O'dee, B. N. Cowan, J. W. Birch, .. Mazzella et al., The use of 1047 resazurin as a novel antimicrobial agent against Francisella tularensis, Front. Cell. Infect. Microbiol. 3, 1048.

V. Siret, D. Barataud, M. Prat, V. Vaillant, S. Ansart et al., An outbreak of 1050 airborne tularaemia in France, Euro Surveill. Bull. Eur. Sur Mal. Transm. Eur. Commun, 2004.

, Dis. Bull, vol.11, pp.58-60

A. Sjostedt, Tularemia: History, Epidemiology, Pathogen Physiology, and Clinical Manifestations, 2007.

, N. Y. Acad. Sci, vol.1105, pp.1-29

M. V. Stundick, M. T. Albrecht, C. R. Houchens, A. P. Smith, T. M. Dreier et al., Animal 1055 Models for Francisella tularensis and Burkholderia Species Scientific and Regulatory Gaps Toward 1056 Approval of Antibiotics Under the FDA Animal Rule, Vet. Pathol. Online, vol.50, pp.877-892, 1057.

V. Sutera, Y. Caspar, S. Boisset, and M. Maurin, A new dye uptake assay to test the activity of 1059 antibiotics against intracellular Francisella tularensis, Front. Cell. Infect. Microbiol, vol.4, 1060.

K. Svensson, E. Back, H. Eliasson, L. Berglund, M. Granberg et al., Landscape 1062 Epidemiology of Tularemia Outbreaks in Sweden, Emerg. Infect. Dis, vol.15, 1063.

K. Svensson, M. Granberg, L. Karlsson, V. Neubauerova, M. Forsman et al., , 2009.

, Time PCR Array for Hierarchical Identification of Francisella Isolates, PLoS ONE, vol.4, 1066.

A. Tarnvik, WHO Guidelines on Tularaemia, 2007.

A. Tärnvik and L. Berglund, Tularaemia. Eur. Respir. J, vol.21, pp.361-373, 1069.

A. Tärnvik and M. C. Chu, New approaches to diagnosis and therapy of tularemia, 2007.

. Sci, , vol.1105, pp.378-404

H. Tomaso, S. Al-dahouk, E. Hofer, W. D. Splettstoesser, T. M. Treu et al., , 2005.

, Antimicrobial susceptibilities of Austrian Francisella tularensis holarctica biovar II strains, Int. J

, Antimicrob. Agents, vol.26, pp.279-284

S. K. Urich and J. M. Petersen, In Vitro Susceptibility of Isolates of Francisella tularensis Types A and 1076 B from North America, Antimicrob. Agents Chemother, vol.52, pp.2276-2278, 2008.

E. Valade, J. Vaissaire, A. Mérens, E. Hernandez, C. Gros et al., Susceptibility of 71 1078 French isolates of Francisella tularensis subsp. holarctica to eight antibiotics and accuracy of the 1079 Etest® method, J. Antimicrob. Chemother, vol.62, pp.208-210, 2008.

K. Velinov, In vitro antimicrobial susceptibility of Francisella tularensis isolated in Bulgaria, Probl. 1081 Infect. Parasit. Dis, vol.39, pp.7-9, 2011.

A. J. Vogler, D. Birdsell, L. B. Price, J. R. Bowers, S. M. Beckstrom-sternberg et al., , 2009.

, Phylogeography of Francisella tularensis: global expansion of a highly fit clone, J. Bacteriol, vol.191, pp.2474-2484

Y. Wang, R. Hai, Z. Zhang, L. Xia, H. Cai et al., Genetic relationship between Francisella 1086 tularensis strains from China and from other countries, Biomed. Environ. Sci. BES, vol.24, pp.310-314, 1087.

Y. Wang, Y. Peng, R. Hai, L. Xia, H. Li et al., Diversity of Francisella tularensis Subsp. 1089 holarctica Lineages, vol.20, 2014.

W. B. Wherry and B. H. Lamb, Infection of Man with Bacterium Tularense, J. Infect. Dis, vol.15, 1914.

A. Sjostedt, Tularemia: history, epidemiology, pathogen physiology, and clinical 391 manifestations, Oyston PC, Sjostedt A, Titball RW, vol.1105, pp.967-978, 2004.

M. Maurin, Francisella tularensis as a potential agent of bioterrorism?, Expert Rev Anti 395 Infect Ther, vol.13, pp.141-144, 2007.

, Acad Sci, vol.1105, pp.378-404

M. Maurin and M. Gyuranecz, Tularaemia: clinical aspects in Europe, Lancet Infect Dis, vol.399, 2016.

S. Boisset, Y. Caspar, V. Sutera, M. Maurin, A. Fabrega et al., New therapeutic approaches for treatment of 401 tularaemia: a review, Front Cell Infect Microbiol, vol.4, pp.40-61, 2009.

J. M. Berger, Type II DNA topoisomerases, Curr Opin Struct Biol, vol.8, pp.26-32, 1998.

L. Scola, B. Elkarkouri, K. Li, W. Wahab, T. Fournous et al., , p.406

C. Robert, S. Audic, S. Lofdahl, D. Raoult, B. M. Loveless et al., Kulesh 410 DA. 2010. Identification of ciprofloxacin resistance by SimpleProbe, High Resolution Melt and 411 Pyrosequencing nucleic acid analysis in biothreat agents: Bacillus anthracis, Yersinia pestis 412 and Francisella tularensis, Mol Cell Probes, vol.18, p.11, 2008.

V. Sutera, M. Levert, W. P. Burmeister, D. Schneider, and M. Maurin, Evolution toward high-414 level fluoroquinolone resistance in Francisella species, J Antimicrob Chemother, vol.69, pp.101-415, 2014.

M. Gellert, K. Mizuuchi, M. H. O'dea, H. A. Nash, K. J. Aldred et al., DNA gyrase: an enzyme that introduces 417 superhelical turns into DNA, Proc Natl Acad Sci U S A, vol.73, pp.3872-3876, 1976.

D. C. Hooper, G. A. Jacoby, L. S. Redgrave, S. B. Sutton, M. A. Webber et al., In vitro susceptibility of isolates of Francisella tularensis types A 426 and B from North America, Mechanisms of drug resistance: quinolone resistance. Ann N Y 421 Acad Sci, vol.424, p.434, 1998.

V. Y. Fofanov, H. Koshinsky, and P. J. Jackson, Identification of Genome-Wide Mutations in 435 Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next 436 Generation Sequencing, PLoS One, vol.11, p.20, 2016.

J. Celli and T. C. Zahrt, Mechanisms of Francisella tularensis intracellular pathogenesis. Cold 438 Spring Harb Perspect Med, vol.3, 2013.

, World Health Organization. WHO guidelines on tularaemia, 2007.

, CDC -Biosafety in Microbiological and Biomedical Laboratories (BMBL), vol.388, 2015.

A. Sjöstedt, Tularemia: history, epidemiology, pathogen physiology, and clinical 390 manifestations, Ann N Y Acad Sci, vol.1105, pp.1-29, 2007.

M. J. Hepburn and A. Simpson, Tularemia: current diagnosis and treatment options, Expert 392 Rev Anti Infect Ther, vol.6, pp.231-271, 2008.

A. Tärnvik and M. C. Chu, New approaches to diagnosis and therapy of tularemia

, Acad Sci, vol.1105, pp.378-404, 2007.

M. E. Evans, D. W. Gregory, W. Schaffner, and Z. A. Mcgee, Tularemia: a 30-year experience 396 with 88 cases, Medicine (Baltimore), vol.64, pp.251-69, 1985.

M. Maurin, I. Pelloux, J. P. Brion, D. Banõ, J. Picard et al., Human tularemia in France, Clin Infect Dis, vol.53, pp.133-141, 2006.
URL : https://hal.archives-ouvertes.fr/hal-00993402

K. A. Feldman, R. E. Enscore, S. L. Lathrop, B. T. Matyas, M. Mcguill et al., An 400 outbreak of primary pneumonic tularemia on Martha's Vineyard, N Engl J Med, vol.401, pp.1601-1607, 2001.

A. Johansson, S. K. Urich, M. C. Chu, A. Sjöstedt, and A. Tärnvik, In vitro susceptibility to 403 quinolones of Francisella tularensis subspecies tularensis, Scand J Infect Dis, vol.404, pp.327-357, 2002.

S. K. Urich and J. M. Petersen, In vitro susceptibility of isolates of Francisella tularensis types 406 A and B from North America, Antimicrob Agents Chemother, vol.52, pp.2276-2284, 2008.

M. Yesilyurt, S. Kiliç, B. Celebi, M. Celik, S. Gül et al., Antimicrobial 408 susceptibilities of Francisella tularensis subsp. holarctica strains isolated from humans 409 in the Central Anatolia region of Turkey, J Antimicrob Chemother, vol.66, pp.2588-92, 2011.

F. C. Origgi, J. Frey, and P. Pilo, Characterisation of a new group of Francisella tularensis 411 subsp. holarctica in Switzerland with altered antimicrobial susceptibilities, Euro Surveill, vol.19, 1996.

M. Maurin, N. F. Mersali, and D. Raoult, Bactericidal activities of antibiotics against 414 intracellular Francisella tularensis, Antimicrob Agents Chemother, vol.44, pp.3428-3459, 2000.

V. Sutera, Y. Caspar, S. Boisset, and M. Maurin, A new dye uptake assay to test the activity of 416 antibiotics against intracellular Francisella tularensis, Front Cell Infect Microbiol, vol.417, p.36, 2014.

M. Nelson, M. S. Lever, R. E. Dean, P. C. Pearce, D. J. Stevens et al., Bioavailability 419 and efficacy of levofloxacin against Francisella tularensis in the common marmoset 420 (Callithrix jacchus), Antimicrob Agents Chemother, vol.54, pp.3922-3928, 2010.

T. Piercy, J. Steward, M. S. Lever, and T. Brooks, In vivo efficacy of fluoroquinolones 422 against systemic tularaemia infection in mice, J Antimicrob Chemother, vol.56, pp.1069-423, 2005.

S. Rotem, E. Bar-haim, H. Cohen, U. Elia, R. Ber et al., Consequences of 425 delayed ciprofloxacin and doxycycline treatment regimens against Francisella tularensis 426 airway infection, Antimicrob Agents Chemother, vol.56, pp.5406-5414, 2012.

I. B. Weber, G. Turabelidze, S. Patrick, K. S. Griffith, K. J. Kugeler et al., Clinical 428 recognition and management of tularemia in Missouri: a retrospective records review of 429 121 cases, Clin Infect Dis, vol.55, pp.1283-90, 2012.

A. Johansson, L. Berglund, A. Sjöstedt, and A. Tärnvik, Ciprofloxacin for treatment of 431 tularemia, Clin Infect Dis, vol.33, pp.267-275, 2001.

, Centers for Disease Control and Prevention (CDC). Tularemia -Missouri, 2000.

, MMWR Morb Mortal Wkly Rep, vol.58, pp.744-752, 2009.

J. L. Pérez-castrillón, P. Bachiller-luque, M. Martín-luquero, and F. J. Mena-martín, Herreros 435 V. Tularemia epidemic in northwestern Spain: clinical description and therapeutic 436 response, Clin Infect Dis, vol.33, pp.573-579, 2001.

M. Meric, A. Willke, E. Finke, R. Grunow, M. Sayan et al., Evaluation of 438 clinical, laboratory, and therapeutic features of 145 tularemia cases: the role of 439 quinolones in oropharyngeal tularemia, APMIS, vol.116, pp.66-73, 2008.

L. S. Redgrave, S. B. Sutton, M. A. Webber, and L. Piddock, Fluoroquinolone resistance: 441 mechanisms, impact on bacteria, and role in evolutionary success, Trends Microbiol, vol.442, pp.438-483, 2014.

V. Sutera, M. Levert, W. P. Burmeister, D. Schneider, and M. Maurin, Evolution toward high-444 level fluoroquinolone resistance in Francisella species, J Antimicrob Chemother, vol.445, pp.101-111, 2013.

B. M. Loveless, A. Yermakova, D. R. Christensen, J. P. Kondig, . Heine-hs-3rd et al., Identification of ciprofloxacin resistance by SimpleProbe, High Resolution Melt 448 and Pyrosequencing nucleic acid analysis in biothreat agents: Bacillus anthracis, p.449

, Yersinia pestis and Francisella tularensis, Mol Cell Probes, vol.24, pp.154-60, 2010.

L. Scola, B. Elkarkouri, K. Li, W. Wahab, T. Fournous et al., Rapid 451 comparative genomic analysis for clinical microbiology: the Francisella tularensis 452 paradigm, Genome Res, vol.18, pp.742-50, 2008.

A. Hotta, O. Fujita, A. Uda, N. Sharma, K. Tanabayashi et al., In vitro 454 antibiotic susceptibility of Francisella tularensis isolates from Japan, Jpn J Infect Dis, vol.455, pp.534-540, 2013.

E. Georgi, E. Schacht, H. C. Scholz, and W. D. Splettstoesser, Standardized broth microdilution 457 antimicrobial susceptibility testing of Francisella tularensis subsp. holarctica strains 458 from Europe and rare Francisella species, J Antimicrob Chemother, vol.67, pp.2429-2462, 2012.

Z. Kreizinger, L. Makrai, G. Helyes, T. Magyar, K. Erdélyi et al., Antimicrobial 460 susceptibility of Francisella tularensis subsp. holarctica strains from Hungary, Central 461 Europe, J Antimicrob Chemother, vol.68, pp.370-373, 2013.

, Performance Standards for Antimicrobial 463 Susceptibility Testing. CLSI document M 100-S20, 2010.

H. Tomaso, A. Dahouk, S. Hofer, E. Splettstoesser, W. D. Treu et al.,

, Antimicrobial susceptibilities of Austrian Francisella tularensis holarctica biovar II 466 strains, Int J Antimicrob Agents, vol.26, pp.279-84, 2005.

B. Gestin, E. Valade, F. Thibault, D. Schneider, and M. Maurin, Phenotypic and genetic 468 characterization of macrolide resistance in Francisella tularensis subsp. holarctica 469 biovar I, J Antimicrob Chemother, vol.65, pp.2359-67, 2010.

S. A. Bustin, V. Benes, J. A. Garson, J. Hellemans, J. Huggett et al., The MIQE 471 guidelines: minimum information for publication of quantitative real-time PCR 472 experiments, Clin Chem, vol.55, pp.611-633, 2009.

J. Weile, E. Seibold, C. Knabbe, M. Kaufmann, and W. Splettstoesser, Treatment of tularemia 474 in patient with chronic graft-versus-host disease, Emerg Infect Dis, vol.19, pp.771-774, 2013.

A. Mailles and V. Vaillant, 10 years of surveillance of human tularaemia in France, Euro 476 Surveill, vol.19, p.20956, 2014.

J. Ruiz, Mechanisms of resistance to quinolones: target alterations, decreased 478 accumulation and DNA gyrase protection, J Antimicrob Chemother, vol.51, pp.1109-1126, 2003.

K. M. Sandoz and D. D. Rockey, Antibiotic resistance in Chlamydiae, Future Microbiol, vol.480, pp.1427-1469, 2010.

L. Shadoud, I. Almahmoud, S. Jarraud, E. J. Larrat, S. Schwebel et al., Hidden 482 Selection of Bacterial Resistance to Fluoroquinolones In Vivo: The Case of Legionella 483 pneumophila and Humans, EBioMedicine, vol.2, pp.1179-85, 2015.

D. Kell, M. Potgieter, and E. Pretorius, Individuality, phenotypic differentiation, dormancy 485 and "persistence" in culturable bacterial systems: commonalities shared by 486 environmental, laboratory, and clinical microbiology, F1000Research, vol.4, p.179, 2015.

X. R. Bina, C. L. Lavine, M. A. Miller, and J. E. Bina, The AcrAB RND efflux system from the live 488 vaccine strain of Francisella tularensis is a multiple drug efflux system that is required 489 for virulence in mice, FEMS Microbiol Lett, vol.279, pp.226-259, 2008.

N. T. Antunes, H. Frase, M. Toth, and S. B. Vakulenko, The class A ?-Lactamase FTU-1 is native to Francisella tularensis, Antimicrob. Agents Chemother, vol.56, pp.666-671, 2012.

J. Denis, C. Jolivalt, M. Maurin, and O. Burchak, Preparation of bisindole derivatives useful as antibacterials, PCT Int. Appl. WO, 2013.

J. Denis, C. Jolivalt, M. Maurin, and M. Jeanty, Preparation of novel bis-indolic derivatives antibacterial drugs and a process for preparing them, PCT Int. Appl. WO, 2013.

D. T. Dennis, T. V. Inglesby, D. A. Henderson, J. G. Bartlett, M. S. Ascher et al., Tularemia as a biological weapon: medical and public health management, JAMA, vol.285, pp.2763-2773, 2001.

C. Dentan, P. Pavese, I. Pelloux, S. Boisset, J. Brion et al., Treatment of tularemia in pregnant woman, France. Emerging Infect. Dis, vol.19, pp.996-998, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00965575

K. England, C. Am-ende, H. Lu, T. J. Sullivan, N. L. Marlenee et al., Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia, J. Antimicrob. Chemother, vol.64, pp.1052-1061, 2009.

B. Gestin, E. Valade, F. Thibault, D. Schneider, and M. Maurin, Phenotypic and Genetic characterization of macrolide resistance in Francisella tularensis subsp. holarctica biovar I, J. Antimicrob. Chemother, vol.65, pp.2359-2367, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00800681

K. E. Hevener, S. Mehboob, P. Su, K. Truong, T. Boci et al., Discovery of a novel and potent class of F. tularensis enoyl-reductase (FabI) inhibitors by molecular shape and electrostatic matching, J. Med. Chem, vol.55, pp.268-279, 2012.

A. Johansson, L. Berglund, L. Gothefors, A. Sjöstedt, and T. A. , Ciprofloxacin for treatment of tularemia in children, Pediatr. Infect. Dis. J, vol.19, pp.449-453, 2000.

A. Johansson, S. K. Urich, M. C. Chu, A. Sjöstedt, and A. Tärnvik, In vitro susceptibility to quinolones of Francisella tularensis subsp. tularensis. Scand, J. Infect. Dis, vol.34, pp.327-330, 2002.

A. Kaya, I. O. Uysal, A. S. Güven, A. Engin, A. Gültürk et al., Treatment failure of gentamicin in pediatric patients with oropharyngeal tularemia, Med. Sci. Monit, vol.17, pp.376-380, 2011.

L. C. Kingry, J. E. Cummings, K. W. Brookman, G. R. Bommineni, P. J. Tonge et al., The Francisella tularensis FabI enoyl-acyl carrier protein reductase gene is essential to bacterial viability and is expressed during infection, J. Bacteriol, vol.195, pp.351-358, 2013.

R. I. Kudelina and N. G. Olsufiev, Sensitivity to macrolide antibiotics and lincomycin in Francisella tularensis holarctica, J. Hyg. Epidemiol. Microbiol. Immunol, vol.24, pp.84-91, 1980.

K. Kumar, D. Awasthi, S. Lee, J. E. Cummings, S. E. Knudson et al., Benzimidazole-based antibacterial agents against Francisella tularensis, Bioorg. Med. Chem, vol.21, pp.3318-3326, 2013.

K. W. Larssen, J. E. Afset, B. T. Heier, T. Krogh, K. Handeland et al., Outbreak of tularaemia in central norway, Euro Surveill, vol.16, 2011.

H. Lu, K. England, C. Am-ende, J. J. Truglio, S. Luckner et al., Slow-onset inhibition of the FabI enoyl reductase from Francisella tularensis: residence time and in vivo activity, ACS Chem. Biol, vol.4, pp.221-231, 2009.

M. Maurin, N. F. Mersali, and D. Raoult, Bactericidal activities of antibiotics against intracellular Francisella tularensis, Antimicrob. Agents Chemother, vol.44, pp.3428-3431, 2000.

M. Maurin, I. Pelloux, J. Brion, J. Del-banõ, and A. Picard, Human tularemia in France, Clin. Infect. Dis, vol.53, pp.133-141, 2006.
URL : https://hal.archives-ouvertes.fr/hal-00993402

S. Mehboob, K. E. Hevener, K. Truong, T. Boci, B. D. Santarsiero et al., Structural and enzymatic analyses reveal the binding mode of a novel series of Francisella tularensis enoyl reductase (FabI) inhibitors, J. Med. Chem, vol.55, pp.5933-5941, 2012.

J. L. Pérez-castrillón, P. Bachiller-luque, M. Martin-luquero, F. J. Mena-martin, and V. Herreros, Tularemia epidemic in northwestern Spain: clinical description and therapeutic response, Clin. Infect. Dis, vol.33, pp.573-576, 2001.

J. F. Petrosino, Q. Xiang, S. E. Karpathy, H. Jiang, S. Yerrapragada et al., Chromosome rearrangement and diversification of Francisella tularensis revealed by the type B (OSU18) genome sequence, J. Bacteriol, vol.188, pp.6977-6985, 2006.

L. Rohmer, M. Brittnacher, K. Svensson, D. Buckley, E. Haugen et al., Potential source of Francisella tularensis live vaccine strain attenuation determined by genome comparison, Infect. Immun, vol.74, pp.6895-6906, 2006.

S. Rotem, E. Bar-haim, H. Cohen, U. Elia, R. Ber et al., Consequences of delayed ciprofloxacin and doxycycline treatment regimens against Francisella tularensis airway infection, Antimicrob. Agents Chemother, vol.56, pp.5406-5408, 2012.

P. Rydén, R. Björk, M. L. Schäfer, J. O. Lundström, B. Petersén et al., Outbreaks of tularemia in a boreal forest region depends on mosquito prevalence, J. Infect. Dis, vol.205, pp.297-304, 2012.

V. Sutera, M. Levert, W. P. Burmeister, D. Schneider, and M. Maurin, Evolution toward high-level fluoroquinolone resistance in Francisella species, 2014.
URL : https://hal.archives-ouvertes.fr/hal-00961489

, J. Antimicrob. Chemother, vol.69, pp.101-110

A. Tärnvik and M. C. Chu, New approaches to diagnosis and therapy of tularemia, Ann. N.Y Acad. Sci, vol.1105, pp.378-404, 2007.

, Conflict of Interest Statement: The authors declare that the research was con

B. Hamad, The antibiotics market, Nat Rev Drug Discov, vol.9, pp.675-681, 2010.

H. W. Boucher, G. H. Talbot, and J. S. Bradley, Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America, Clin Infect Dis, vol.48, pp.1-12, 2009.

S. J. Projan, Why is big Pharma getting out of antibacterial drug discovery?, Curr Opin Microbiol, vol.6, pp.427-457, 2003.

J. L. Munoz-bellido, M. Manzanares, and J. Andres, Efflux pumpmediated quinolone resistance in Staphylococcus aureus strains wild type for gyrA, gyrB, grlA, and norA, Antimicrob Agents Chemother, vol.43, pp.354-360, 1999.

M. Tanaka, T. Wang, and Y. Onodera, Mechanism of quinolone resistance in Staphylococcus aureus, J Infect Chemother, vol.6, pp.131-140, 2000.

G. W. Kaatz, S. M. Seo, and C. A. Ruble, Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus, Antimicrob Agents Chemother, vol.37, pp.1086-94, 1993.

S. J. Van-hal, T. P. Lodise, and D. L. Paterson, The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis, Clin Infect Dis, vol.54, pp.755-71, 2012.

S. J. Van-hal and V. G. Fowler, Is it time to replace vancomycin in the treatment of methicillin-resistant Staphylococcus aureus infections?, Clin Infect Dis, vol.56, pp.1779-88, 2013.

K. Lewis, Antibiotics: recover the lost art of drug discovery, Nature, vol.485, pp.439-479, 2012.

K. Kumar and S. Chopra, New drugs for methicillin-resistant Staphylococcus aureus: an update, J Antimicrob Chemother, vol.68, pp.1465-70, 2013.

R. P. Wenzel, The antibiotic pipeline: challenges, costs, and values, N Engl J Med, vol.351, pp.523-529, 2004.

K. J. Shaw and M. R. Barbachyn, The oxazolidinones: past, present, and future

, Ann N Y Acad Sci, vol.1241, pp.48-70, 2011.

C. Vilhena and A. Bettencourt, Daptomycin: a review of properties, clinical use, drug delivery and resistance, Mini Rev Med Chem, vol.12, pp.202-211, 2012.

L. Robbel and M. A. Marahiel, Daptomycin, a bacterial lipopeptide synthesized by a nonribosomal machinery, J Biol Chem, vol.285, pp.27501-27509, 2010.

A. S. Bayer, T. Schneider, and H. Sahl, Mechanisms of daptomycin resistance in Staphylococcus aureus: role of the cell membrane and cell wall, Ann N Y Acad Sci, vol.1277, pp.139-58, 2013.

K. S. Long and B. Vester, Resistance to linezolid caused by modifications at its binding site on the ribosome, Antimicrob Agents Chemother, vol.56, pp.603-615, 2012.

W. Gul and M. T. Hamann, Indole alkaloid marine natural products: an

X. Guinchard, Chimie des nitrones: applications en synthèse organique et a ` la synthè se de composé s bio-actifs, 2006.

K. Oh, W. Mar, and S. Kim, Antimicrobial activity and cytotoxicity of bis(indole) alkaloids from the sponge Spongosorites sp, Biol Pharm Bull, vol.29, pp.570-573, 2006.

X. Guinchard, Y. Vallée, and J. Denis, Total syntheses of brominated marine sponge alkaloids, Org Lett, vol.9, pp.3761-3765, 2007.

X. Guinchard, Y. Vallé-e, and J. Denis, Total synthesis of marine sponge bis(indole) alkaloids of the topsentin class, J Org Chem, vol.72, pp.3972-3977, 2007.

O. N. Burchak, E. L. Pihive, and L. Maigre, Synthesis and evaluation of 1-(1H-indol-3-yl)ethanamine derivatives as new antibacterial agents
URL : https://hal.archives-ouvertes.fr/hal-00801247

, Bioorg Med Chem, vol.19, pp.3204-3219, 2011.

A. Hequet, O. N. Burchak, and M. Jeanty, 1-(1H-Indol-3-yl)ethanamine derivatives as potent Staphylococcus aureus NorA efflux pump inhibitors, ChemMedChem, vol.9, pp.1534-1579, 2014.
URL : https://hal.archives-ouvertes.fr/hal-00986364

J. Denis, X. Guinchard, and N. Moreau, Synthesis of new indole derivatives, their preparation processes, and their antibacterial uses, PCT Int Appl, 2008.

J. Denis, C. Jolivalt, and M. Maurin, Preparation of novel bis-indolic derivatives antibacterial drugs and a process for preparing them, PCT Int Appl, 2013.

J. Denis, C. Jolivalt, and M. Maurin, Preparation of bis-indole derivatives useful as antibacterials, PCT Int Appl, 2013.

M. Bergeron, O. Dauwalder, and M. Gouy, Species identification of staphylococci by amplification and sequencing of the tuf gene compared to the gap gene and by matrix-assisted laser desorption ionization timeof-flight mass spectrometry, Eur J Clin Microbiol Infect Dis, vol.30, pp.343-54, 2011.

S. Sabatini, F. Gosetto, and G. Manfroni, Evolution from a natural flavones nucleus to obtain 2-(4-propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump, J Med Chem, vol.54, pp.5722-5758, 2011.

, Methods for Determining Bactericidal Activity of Antimicrobial Agents: Approved Guideline M26-A. NCCLS, 1999.

J. Oravcova, B. Bö-hs, and W. Lindner, Drug-protein binding studies new trends in analytical and experimental methodology, J Chromatogr B Biomed Sci App, vol.677, pp.1-28, 1996.

K. Valko, C. Du, and C. Bevan, Rapid method for the estimation of octanol/water partition coefficient (log P oct ) from gradient RP-HPLC retention and a hydrogen bond acidity term (Sigma alpha2H), Curr Med Chem, vol.8, pp.1137-1183, 2001.

I. M. Gould, R. Cauda, and S. Esposito, Management of serious meticillinresistant Staphylococcus aureus infections: what are the limits?, Int J Antimicrob Agents, vol.37, pp.202-211, 2011.

B. Bao, Q. Sun, and X. Yao, Bisindole alkaloids of the topsentin and hamacanthin classes from a marine sponge Spongosorites sp, J Nat Prod, vol.70, pp.2-8, 2007.

A. Casapullo, G. Bifulco, and I. Bruno, New bisindole alkaloids of the topsentin and hamacanthin classes from the Mediterranean marine sponge Rhaphisia lacazei, J Nat Prod, vol.63, pp.447-51, 2000.

S. P. Gunasekera, P. J. Mccarthy, and M. Kelly-borges, Hamacanthins A and B, new antifungal bis indole alkaloids from the deep-water marine sponge, Hamacantha sp, J Nat Prod, vol.57, pp.1437-1478, 1994.

B. Bao, Q. Sun, and X. Yao, Cytotoxic bisindole alkaloids from a marine sponge Spongosorites sp, J Nat Prod, vol.68, pp.711-716, 2005.

A. E. Wright, S. A. Pomponi, and S. S. Cross, A new bis-(indole) alkaloid from a deep-water marine sponge of the genus Spongosorites, J Org Chem, vol.57, pp.4772-4777, 1992.

R. Zoraghi, L. Worrall, and R. H. See, Methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as a target for bis-indole alkaloids with antibacterial activities, J Biol Chem, vol.286, pp.44716-44741, 2011.

R. G. Panchal, R. L. Ulrich, and D. Lane, Novel broad-spectrum bis-(imidazolinylindole) derivatives with potent antibacterial activities against antibioticresistant strains, Antimicrob Agents Chemother, vol.53, pp.4283-91, 2009.

M. M. Butler, J. D. Williams, and N. P. Peet, Comparative in vitro activity profiles of novel bis-indole antibacterials against Gram-positive and Gram-negative clinical isolates, Antimicrob Agents Chemother, vol.54, pp.3974-3981, 2010.

R. G. Panchal, D. Lane, and H. I. Boshoff, Bis-imidazolinylindoles are active against methicillin-resistant Staphylococcus aureus and multidrug-resistant Mycobacterium tuberculosis, J Antibiot, p.2013

M. R. Jacobs, S. Bajaksouzian, and C. E. Good, Novel bis-indole agents active against multidrug-resistant Acinetobacter baumannii, Diagn Microbiol Infect Dis, vol.69, pp.114-120, 2011.

G. S. Kumar, S. Kumaresan, M. Prabhu, and A. A. , An efficient one pot syntheses of aryl-3,3 ? -bis(indolyl)methanes and studies on their spectral characteristics, DPPH radical scavenging-, antimicrobial-, cytotoxicity-, and antituberculosis activity, Spectrochim Acta A Mol Biomol Spectrosc, vol.101, pp.254-63, 2013.

M. Mielczarek, R. V. Devakaram, and C. Ma, Synthesis and biological activity of novel bis-indole inhibitors of bacterial transcription initiation complex formation, Org Biomol Chem, vol.12, pp.2882-94, 2014.

K. Oh, W. Mar, and S. Kim, Bis(indole) alkaloids as sortase A inhibitors from the sponge Spongosorites sp, Bioorg Med Chem Lett, vol.15, pp.4927-4958, 2005.

R. Zoraghi, R. H. See, and P. Axerio-cilies, Identification of pyruvate kinase in methicillin-resistant Staphylococcus aureus as a novel antimicrobial drug target, Antimicrob Agents Chemother, vol.55, pp.2042-53, 2011.

P. Axerio-cilies, R. H. See, and R. Zoraghi, Cheminformatics-driven discovery of selective, nanomolar inhibitors for staphylococcal pyruvate kinase

, ACS Chem Biol, vol.7, pp.350-359, 2012.

N. S. Kumar, E. M. Dullaghan, and B. B. Finlay, Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections, Bioorg Med Chem, vol.22, pp.1708-1733, 2014.

N. S. Kumar, E. A. Amandoron, and A. Cherkasov, Optimization and structure -activity relationships of a series of potent inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as novel antimicrobial agents, Bioorg Med Chem, vol.20, pp.7069-82, 2012.

Y. Caspar, V. Sutera, and S. Boisset, Bis-indolic compounds as potential new therapeutic alternatives for tularaemia, Front Cell Infect Microbiol, vol.4, p.24, 2014.
URL : https://hal.archives-ouvertes.fr/hal-00964947

P. N. Markham, E. Westhaus, and K. Klyachko, Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus, Antimicrob Agents Chemother, vol.43, pp.2404-2412, 1999.

S. S. Costa, C. Falcã-o, and M. Viveiros, Exploring the contribution of efflux on the resistance to fluoroquinolones in clinical isolates of Staphylococcus aureus, BMC Microbiol, vol.11, p.241, 2011.

S. Samosorn, B. Tanwirat, and N. Muhamad, Antibacterial activity of berberine-NorA pump inhibitor hybrids with a methylene ether linking group, Bioorg Med Chem, vol.17, pp.3866-72, 2009.

, carboxamido)ethyl]carbamate 9b Prepared according to the above general procedure from indolic diamine 7b (60 mg, 0.169 mmol), 1H-indole-3-carboxylic acid 8a (27 mg, 0.169 mmol) and DCC (38 mg, 0.186 mmol) in CH2Cl2 (5 mL). After purification, the compound 9b (62 mg, 0.125 mmol, 73%) was obtained as a white solid

. Mhz, CD3OD): ? = 1.35 (s, 9H), 3.58-3.70 (m, 2H), 5.56-5.60 (m, 1H), 7.12-7.19 (m, 3H), 7.27 (d, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.90-7.92 (m, 2H), 8.11 (d, J = 7.6 Hz, 1H) ppm. 13 C NMR (100 MHz, CD3OD): ?? = 28.7 (C(CH3)3), vol.3392, pp.24-25, 1169.

, -yl)-2-(5-bromo-1H-indol-3-yl-carboxamido)ethyl? carbamate 9c Prepared according to the above general procedure from indolic diamine 7a (150 mg, 0.545 mmol), 5-bromo-1H-indole-3-carboxylic acid 8b (131 mg, 0.545 mmol) and EDCI (110 ?L, 0.599 mmol) in THF (8 mL). After purification, the compound 9c (195 mg, 0.392 mmol, 72%) was obtained as a white solid

. Mhz, CD3OD): ? = 1.35 (s, 9H), 3.60-3.74 (m, 2H), 5.62-5.66 (m, 1H), 6.99-7.05 (m, 1H), 7.08-7.13 (m, 1H), vol.80

, M+Na) + ?. HRMS (ESI + ) calcd for C24H25N4O3BrNa [(M+Na) + ]: 519.1002 and 521.0985. Found: 519.1004 and 521.0982. tert-Butyl ?2-(6-bromo-1H-indol-3-yl)-2-(1H-indolyl-3-carboxamido)ethyl? carbamate 9d Prepared according to the above general procedure from indolic diamine 7c (60 mg, 0.169 mmol), 1H-indole-3-carboxylic acid 8a and EDCI (33 ?L, 0.186 mmol) in THF (4 mL), LRMS (ESI + ): m/z = 519 and 521, vol.3309, pp.739-740, 1166.

, LRMS (ESI + ): m/z =, vol.807, p.499, 1163.

+. , Found: 519.1005 and 521.0983. tert-Butyl ?2-(1H-indol-3-yl)-2-(6-bromo-1H-indolyl-3-carboxamido)ethyl? carbamate 9e Prepared according to the above general procedure from indolic diamine 7a (60 mg, 0.218 mmol), 6-bromo-1H-indole-3-carboxylic acid 8c (53 mg, 0.218 mmol) and EDCI (45 ?L, 0.248 mmol) in THF (4 mL), vol.519, p.521

. Mhz, CH2), 48.6 (CHN), 80.2 (C(CH3)3), 112.2 (C, CD3OD): ? = 1.35 (s, 9H), 3.63-3.72 (m, 2H), 5.62-5.65 (m, 1H), 7.01 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), vol.7, pp.737-738, 1160.

, After purification, the compound 9f (67 mg, 0.116 mmol, 68%) was obtained as a white solid

. Mhz, CD3OD): ? = 1.35 (s, 9H), 3.56-3.71 (m, 2H), 5.55-5.59 (m, 1H), vol.7

, LRMS (ESI + ): m/z = 597, vol.48, p.601, 1164.

, HRMS (ESI + ) calcd for C24H24N4O3Br2Na

, After purification, the compound 9g (84 mg, 0.146 mmol, 65%) was obtained as a white solid

. Mhz, CD3OD): ? = 1.35 (s, 9H), 3.58-3.69 (m, 2H), 5.55-5.58 (m, 1H), 7.18-7.27 (m, 3H), vol.7

. Mhz, CD3OD): ? = 28.7 (C(CH3)3), 45.6 (CH2), vol.48, p.601, 1277.

, mmol) and EDCI (22 ?L, 0.124 mmol) in THF (3 mL). After purification, the compound 9h (34 mg, 0.059 mmol, 52%) was obtained as a white solid

. Mhz, CD3OD): ? = 1.35 (s, 9H), 3.61-3.71 (m, 2H), 5.59-5.65 (m, 1H), 7.12 (dd, J = 1.7 and 8.5 Hz, 1H), 7.24-7.34 (m, 3H), 7.51 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.92 (s, 1H), 8.32 (br s, 1H) ppm. 13 C NMR (75.5 MHz, CD3OD): ? = 28.7 (C(CH3)3), 45.6 (CH2), vol.48, pp.788-789, 1162.

, LRMS (ESI + ): m/z = 597, 599 and 601 [(M+Na) + ?. HRMS (ESI + ) calcd for C24H24N4O3Br2Na

, After purification, the compound 9i (54 mg, 0.094 mmol, 47%) was obtained as a white solid

. Mhz, 89 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H) ppm, CD3OD): ? = 1.35 (s, 9H), 3.60-3.71 (m, 2H), 5.58-5.63 (m, 1H), 7.12 (dd, J = 1.5 and 8.5 Hz, 1H), 7.24 (dd, J = 1.5 and 8.6 Hz, 1H), 7.29 (s, 1H), 7.51 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), vol.7, pp.24-24, 1161.

, After purification, the compound 9j (110 mg, 0.226 mmol, 75%) was obtained as beige foam. 1 H NMR (300 MHz, CDCl3): ? = 1.36 (s, 9H), .60 (m, 2H), 5.22-5.28 (m, 1H), 5.38-5.43 (m, 1H), pp.3-56

, HRMS (ESI + ) calcd for C24H25Cl2N4O3, LRMS (ESI + ): m/z (%) = 509 (39) [(M+Na) + ?, p.237

, After purification, the compound 9k (90 mg, 0.185 mmol, 62%) was obtained as beige foam. 1 H NMR (300 MHz, CDCl3): ? = 1.36 (s, 9H), .63 (m, 2H), 5.22-5.28 (m, 1H), 5.40-5.45 (m, 1H), 6.89-7.19 (m, 6H), 7.42-7.54 (m, 2H), 7.96-8.01 (s, 1H), vol.9, pp.3-57

, HRMS (ESI + ) calcd for C24H25Cl2N4O3, LRMS (ESI + ): m/z (%) =, vol.509, p.237

-. Bromo, carboxamide 10a Prepared according to the above general procedure from indolic amine 7e (150 mg, 0.627 mmol), 5-bromo-1H-indole-3-carboxylic acid 8b (150 mg, 0.627 mmol) and EDCI (107 mg, 0.690 mmol) in THF (10 mL), Mp: 144°C. 1 H NMR

1. Hz, C. H. )-;-m, 3. , and C. ). , 82 (s, 1H, CH), 8.12 (d, J = 2.4 Hz, 1H, NH), 8.16 (d, J = 8.4 Hz, 1H, CH), 8.38 (s, 1H, CH), 11.11 (br s, 1H, NH), 11.70 (br s, 1H, NH) ppm. 13 C NMR (100 MHz, DMSO-d6): ? = 20, vol.7, pp.1205-1206

, LRMS (ESI -): m/z = 458, 460 and 462

, After purification, the compound 10b (60 mg, 0.150mmol, 50%) was obtained as beige foam. Yield: 50%. 1 H NMR (300 MHz, CD3OD-DMSO-d6): ? = 1.60 (d, J = 6.8 Hz, 3H), 5.49 (q, J = 6.8 Hz, 1H), 6.87 (dt, J = 2.6 and 9.0 Hz, 1H), 6.99 (dt, J = 2.6 and 9, 459.9655, 461.9635 and 463.9617. Found: 459.9646, 461.9631 and 463.9612. N-?1-(5-Bromo-1H-indol-3-yl)ethyl?-5-fluoro-1H-indole-3-carboxamide 10b Prepared according to the above general procedure from indolic amine 7e (72 mg, 0.300 mmol), vol.8, p.760, 0930.

3. , 81 (s, 3H, CH3), 5.44-5.50 (m, 1H, CH), 6.92 (br s, 1H, NH), 7.17 (dd, J = 2.0 and 8.4 Hz, DMSO-d6): ? = 1.32 (s, 9H, CH3), 3.40-3.54 (m, 2H, CH2), vol.3

, 3 (CH), CH3), 44.2 (CH2), 45.1 (CH), 77.6 (C), 109.1 (C), 111.7 (C, vol.112

. Ir-(atr, HRMS (ESI + ) calcd for C25H27Br2N4O3, vol.3271, p.419, 1231.

M. Duflos, M. Nourrisson, J. Brelet, J. Courant, G. Lebaut et al., N-Pyridinyl-indole-3-(alkyl)carboxamides and derivatives as potential systemic and topical inflammation inhibitors, Eur J Med Chem, vol.36, pp.545-53, 2001.

O. Ilovich, H. Billauer, S. Dotan, and E. Mishani, Labeled 3-aryl-4-indolylmaleimide derivatives and their potential as angiogenic PET biomarkers, Yield: 81%. 1 H NMR (300 MHz, vol.18, pp.612-632, 2010.

, 178.3 (C) ppm. LRMS (ESI -): m/z =, vol.139, p.282

, Found: 281.9762 and 283.9742. Methyl 2-(5-bromo-1H-indol-3-yl)-2-(hydroxyimino)acetate A vial was charged with the keto-ester previously obtained, HRMS (ESI + ) calcd for C11H9BrNO3

, mmol) as a red-brown solid (2 isomers, ratio, 1/1). Yield: 54%

H. Nmr, 50 (s, 1H, CH), 8.02 (s, 1H, CH), 400 MHz, DMSO-d6): ? = 3.83 (s, 3H, CH3), 7.27 (d, J = 8.8 Hz, 1H, CH), 7.42 (d, J = 8.8 Hz, 1H, CH), vol.7

, 55 (s, 1H, CH), 8.13 (d, J = 1.6 Hz, 1H, CH), 11.31 (s, 1H, OH), 11.79 (br s, 1H, NH) ppm. 13 C NMR (100 MHz, DMSO-d6): ? = 62.3 (CH3), 113.5 (C), ? = 3.87 (s, 3H, CH3), 7.32 (d, J = 8.8 Hz, 1H, CH), 7.42 (d, J = 8.8 Hz, 1H, CH), vol.7, pp.1106-1107, 1235.

, LRMS (ESI -): m/z = 295 and 297

, HRMS (ESI + ) calcd for C11H10BrN2O3

, DMSO-d6): ? = 2.21 (br s, 2H, NH2), The indolic oxime previously obtained (1.67 g, 5.62 mmol) was dissolved in THF (30 mL). . Yield: 74%. 1 H NMR (400 MHz

, DMSO-d6): ? = 51.3 (CH), 51.6 (CH3), 111.2 (C), vol.113

, LRMS (ESI -): m/z = 281 and 283

, HRMS (ESI + ) calcd for C11H9BrN2O2

, Found: 265.9815 and 267.9795. Methyl 2-(5-bromo-1H-indol-3-yl)-2-(5-bromo-1H-indole-3-carboxamido)acetate 14a

, 00 mmol) was dissolved in 50 mL of THF. To this solution, 5-bromo-1H-indole-solid. Yield: 75%. The solid was washed with pentane to remove traces of ethyl acetate (1.10 g, 2.18 mmol)

H. Nmr, 300 MHz, DMSO-d6): ? = 3.67 (s, 3H, CH3), 5.82 (d, J = 6.0 Hz, 1H, CH), 7.24 (dd, J = 1.8 and 6.6 Hz, 1H, CH), 7.28 (dd, J = 2.1 and 8.7 Hz, 1H, CH), 7.39 (d, J = 8.7 Hz, 1H, CH), 7.41 (d, J = 8.7 Hz, 1H, CH), 7.53 (d, J = 2.4 Hz, 1H, CH), vol.7

?. , , vol.49

, (C), 171.6 (C) ppm. IR (ATR): 3223, 3031, LRMS (ESI -): m/z = 501, vol.121, p.505, 1372.

, 503.9553, 505.9534, and 507.9517. Found: 503.9547, 505.9529 and 507.9510. 2

. Mhz and . Dmso-d6, CH), 7.53 (d, J = 2.4 Hz, 1H, CH), 7.84 (d, J = 2.0 Hz, 1H, CH), 8.31 (d, J = 2.4 Hz, 1H, CH), 8.35 (d, J = 2.0 Hz, 1H, CH), 8.46 (d, J = 6.8 Hz, 1H, NH), 11.37 (br s, 1H, NH), 11.78 (br s, 1H, NH), 12.54 (br s, 1H, OH) ppm. 13 C NMR (100 MHz, DMSO-d6): ?, vol.1, p.3406, 1187.

, HRMS (ESI + ) calcd for C19H14Br2N3O3, vol.9396, p.489

, 86 (d, J = 1.8 Hz, 1H, CH), 8.06 (d, J = 1.8 Hz, 1H, NH), 8.17 (s, 1H, CH), 8.33 (d, J = 2.1 Hz, 1H, CH), 6.3 and 8.4 Hz, 1H, CH), 7.16 (dd, J = 1.8 and 8.7 Hz, 1H, CH), 7.26 (dd, J = 2.1 and 8.4 Hz, 1H, CH), 7.33 (d, J = 8.4 Hz, 1H, CH), 7.37 (s, 1H, CH), 7.40 (d, J = 8.7 Hz, 1H, CH), vol.7, pp.1041-1042, 1204.

, LRMS (ESI -): m/z = 474, vol.476, p.478

, HRMS (ESI + ) calcd for C19H16Br2N3O2

, Found: 475.9600, 477.9580 and 479.9561. Synthesis of bis-indole molecules 15a-c

, -hydroxylethyl)amino)-2-oxoethyl)-1H-indole-3-carboxamide 15a A vial was charged with the ester 14a (50 mg, 0.100 mmol), potassium carbonate, vol.27

, Yield: 75%. Mp: 164°C. 1 H NMR (300 MHz, DMSO-d6): ? = 3.15-3.24 (m, 2H, CH2), 3.40-3.46 (m, 2H, CH2), 4.65 (t, J = 5.4 Hz, 1H, OH), 5.92 (d, J = 7.8 Hz, 1H, CH), 7.19 (dd, J = 2.1 and 8.7 Hz, 1H, CH), 7.27 (dd, J = 2.1 and 8.7 Hz, vol.1

, 111.3 (C), 112.2 (C), 113.2 (C), 113.4 (CH), 113.8 (C), 121.4 (CH), 123.1 (CH), vol.123, pp.1194-1195, 1455.

, HRMS (ESI + ) calcd for C21H19Br2N4O3

, -hydroxybutyl)amino)-2-oxoethyl)-1H-indole-3-carboxamide 15b A vial was charged with the ester 14a (50 mg, 0.100 mmol), potassium carbonate (27 mg, 0.200 mmol)

, mg, 0.066 mmol). Yield: 66%. Mp: 187°C. 1 H NMR (400 MHz, DMSO-d6): ? = 1.36-1.47 (m, 4H, CH2), 3.08-3.13 (m, 2H, CH2)

1. Hz and C. ). , , vol.1

, M+H) + ]: 561.0131, 563.0112 and 565.0096. Found: 561.0125, 563.0107 and 565.0090, m, 2H, CH2), 5.34-5.40 (m, 1H, CH), 6.98 (t, J = 5.6 Hz, 1H, NH), 7.19 (d, J = 8.4 Hz, 1H, CH), 7.31 (d, J = 8.8 Hz, 1H, CH, vol.123, pp.1149-1150, 1226.

, In a dry flask under argon, the indolic amine 11 (100 mg

D. Mhz, M. E. Evans, D. W. Gregory, W. Schaffner, and Z. A. Mcgee, 86 (s, 1H, CH), 8.34 (d, J = 2.1 Hz, 1H, CH), 8.74 (s, 1H, CH), 8.94 (d, J = 8.8 Hz, 1H, NH), 11.15 (br s, 1H, NH), 12.41 (br s, 1H, NH) ppm. 13 C NMR (75.5 MHz, DMSO-d6): ? = 20.3 (CH3), 40.6 (CH), 111.2 (C), 3H, CH3), 5.34-5.44 (m, 1H, CH), 7.17 (d, J = 8.4 Hz, 1H, CH), 7.32-7.41 (m, 3H, CH), 7.52 (d, J = 8.4 Hz, 1H, CH), vol.7, pp.251-69, 1229.

H. Syrjälä, R. Schildt, and S. Räisäinen, In vitro susceptibility of Francisella tularensis to fluoroquinolones and treatment of tularemia with norfloxacin and ciprofloxacin, Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol, vol.10, issue.2, pp.68-70, 1991.

M. Maurin, I. Pelloux, J. P. Brion, J. Banõ, and A. Picard, Human Tularemia in France, Clin Infect Dis, vol.53, issue.10, pp.133-174, 2006.
DOI : 10.1093/cid/cir612
URL : https://hal.archives-ouvertes.fr/hal-00993402

A. Sjostedt and . Tularemia, History, Epidemiology, Pathogen Physiology, and Clinical Manifestations, Ann N Y Acad Sci, vol.1105, issue.1, pp.1-29, 2007.

S. Ohara, Studies on yato-byo (Ohara's disease, tularemia in Japan). I, Jpn J Exp Med, vol.24, issue.2, pp.69-79, 1954.

A. N. Weinberg, W. B. Commentary:-wherry, and B. H. Lamb, Infection of man with Bacterium tularense, J Infect Dis, vol.15, issue.7, pp.1317-1337, 1914.

G. Mccoy, Plague-like disease in rodents, Public Health Bull, issue.43, pp.53-71, 1911.

A. Tärnvik, L. Berglund, and . Tularaemia, Eur Respir J, vol.21, issue.2, pp.361-73, 2003.

S. R. Telford and H. K. Goethert, Toward an Understanding of the Perpetuation of the Agent of Tularemia. Front Microbiol, 2011.

G. W. Mccoy and C. W. Chapin, Further Observations on a Plague-Like Disease of Rodents with a Preliminary Note on the Causative Agent, Bacterium Tularense, J Infect Dis, vol.10, issue.1, pp.61-72, 1912.

W. B. Wherry and B. H. Lamb, Infection of Man with Bacterium Tularense, J Infect Dis, vol.15, issue.2, pp.331-371, 1914.

W. B. Wherry, A New Bacterial Disease of Rodents: Transmissible to Man. Public Health Rep 1896-1970, vol.29, pp.3387-90, 1914.
DOI : 10.1097/00007611-191507000-00035

E. Francis, R. Pike, and . Md-b, Weekly Reports for SEPTEMBER 12, Public Health Rep, vol.34, issue.37, p.2061, 1919.

E. Francis, B. Mayne, and G. C. Lake, Tularaemia Francis 1921 a new disease of man, Washington: Govt. Print. Off, 1922.

E. Francis, A summary of present knowledge of tularaemia, 1928.

R. R. Parker, Recent studies of tick borne diseases made at the U.S. Public Health Service Laboratories at Hamilton, MT. Proceedings of 5th Pacific Science Congress, pp.3367-3374, 1934.

R. R. Parker, R. R. Spencer, and E. Francis, Tularemia infection in ticks of the species Dermacentor andersoni stiles in the Bitterroot Valley, Montana. Public Health Rep, pp.1057-1073, 1924.

C. B. Philip and W. L. Jellison, The American dog tick, Dermacentor variabilis, as a host of Bacterium tularense, Public Health Rep, pp.386-92, 1934.

H. Ohara, Experimental inoculation of disease of wild rabbits into the human body, and its bacteriological study, Jpn Med World, pp.299-304, 1926.

K. Oshio, M. Hisayuki, I. Kiyoaki, S. Masao, and O. Shoichiro, Studies on the Skin Test of Yato-Byo (Ohara's Disease, Tularemia in Japan), Ohoku J Exper Med, pp.268-73, 1921.

J. Ellis, P. Oyston, M. Green, R. W. Titball, and . Tularemia, Clin Microbiol Rev, vol.15, issue.4, pp.631-677, 2002.

S. Rockwood and . Tularemia, What's in a name, ASM News, pp.63-68, 1983.

D. B. Ritter and R. K. Gerloff, Deoxyribonucleic acid hybridization among some species of the genus Pasteurella, J Bacteriol, vol.92, issue.6, p.1838, 1966.

N. G. Olsufiev, O. S. Emelyanova, and T. N. Dunayeva, Comparative study of strains of B. tularense in the old and new world and their taxonomy, J Hyg Epidemiol Microbiol Immunol, vol.3, pp.138-187, 1959.

W. L. Jellison, Tularemia in North America, pp.1930-1974, 1974.

W. L. Jellison and C. R. Owen, Tularemia and animal populations ecology and epizootiology. West Salem, Wis.: Microcard, 1961.

N. G. Olsufjev, Taxonomy and characteristic of the genus Francisella Dorofeev, J Hyg Epidemiol Microbiol Immunol, vol.14, issue.1, pp.67-74, 1947.

N. G. Olsufjev and I. S. Meshcheryakova, Subspecific Taxonomy of Francisella tularensis McCoy and Chapin 1912, Int J Syst Bacteriol, vol.33, issue.4, pp.872-876, 1983.

R. I. Kudelina and N. G. Olsufiev, Sensitivity to macrolide antibiotics and lincomycin in Francisella tularensis holarctica, J Hyg Epidemiol Microbiol Immunol, vol.24, issue.1, pp.84-91, 1980.

N. G. Olsufjev and I. S. Meshcheryakova, Infraspecific taxonomy of tularemia agent Francisella tularensis McCoy et Chapin, J Hyg Epidemiol Microbiol Immunol, vol.26, issue.3, pp.291-300, 1982.

A. J. Vogler, D. Birdsell, L. B. Price, J. R. Bowers, S. M. Beckstrom-sternberg et al., Phylogeography of Francisella tularensis: global expansion of a highly fit clone, J Bacteriol, vol.191, issue.8, pp.2474-84, 2009.

S. Kiliç, B. Çelebi, B. Acar, and M. Ata?, In vitro susceptibility of isolates of Francisella tularensis from Turkey, Scand J Infect Dis, vol.45, issue.5, pp.337-378, 2013.

Y. Wang, Y. Peng, R. Hai, L. Xia, H. Li et al., Diversity of Francisella tularensis Subsp. holarctica Lineages, China. Emerg Infect Dis, 2014.

J. W. Conlan, Francisella tularensis: A Red-blooded Pathogen, J Infect Dis, vol.204, issue.1, pp.6-8, 2011.

D. T. Dennis, T. V. Inglesby, and D. A. Henderson, Tularemia as a biological weapon: Medical and public health management, JAMA, vol.285, issue.21, pp.2763-73, 2001.

, Health aspects of chemical and biological weapons, 1970.

R. R. Chaudhuri, C. Ren, L. Desmond, A. Vincent, G. Silman et al., Genome Sequencing Shows that European Isolates of Francisella tularensis Subspecies tularensis Are Almost Identical to US Laboratory Strain Schu S4, PLoS ONE, 2007.
DOI : 10.1371/journal.pone.0000352
URL : https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000352&type=printable

J. Jackson, A. Mcgregor, L. Cooley, J. Ng, M. Brown et al., Francisella tularensis Subspecies holarctica, Emerg Infect Dis, vol.18, issue.9, pp.1484-1490, 2011.

S. Mohamed, A. I. Mubarak, and A. Lo, Francisella tularensis Bacteremia: A Case Report from Sudan. Case Rep Infect Dis, 2012.
DOI : 10.1155/2012/405737
URL : http://downloads.hindawi.com/journals/criid/2012/405737.pdf

O. Fujita, A. Uda, A. Hotta, A. Okutani, S. Inoue et al., Genetic diversity of Francisella tularensis subspecies holarctica strains isolated in Japan, Microbiol Immunol, vol.52, issue.5, pp.270-276, 2008.
DOI : 10.1111/j.1348-0421.2008.00036.x
URL : https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1348-0421.2008.00036.x

E. Karlsson, I. Golovliov, A. Lärkeryd, M. Granberg, E. Larsson et al., Clonality of erythromycin resistance in Francisella tularensis, J Antimicrob Chemother, p.235, 2016.
DOI : 10.1093/jac/dkw235
URL : https://academic.oup.com/jac/article-pdf/71/10/2815/17430231/dkw235.pdf

A. Sjödin, K. Svensson, C. Öhrman, J. Ahlinder, P. Lindgren et al., Genome characterisation of the genus Francisella reveals insight into similar evolutionary paths in pathogens of mammals and fish, BMC Genomics, vol.13, p.268, 2012.

M. E. Brett, L. B. Respicio-kingry, S. Yendell, R. Ratard, J. Hand et al., Outbreak of Francisella novicida Bacteremia Among Inmates at a Louisiana Correctional Facility, Clin Infect Dis Off Publ Infect Dis Soc Am, 2014.

D. N. Birdsell, T. Stewart, A. J. Vogler, E. Lawaczeck, A. Diggs et al., Francisella tularensis subsp. novicida isolated from a human in Arizona, BMC Res Notes, vol.2, p.223, 2009.

L. C. Kingry and J. M. Petersen, Comparative review of Francisella tularensis and Francisella novicida. Front Cell Infect Microbiol, 2014.
DOI : 10.3389/fcimb.2014.00035
URL : https://www.frontiersin.org/articles/10.3389/fcimb.2014.00035/pdf

H. Busse, B. Huber, P. Anda, R. Escudero, H. C. Scholz et al., Objections to the transfer of Francisella novicida to the subspecies rank of Francisella tularensis -response to Johansson et al, Int J Syst Evol Microbiol, vol.60, pp.1718-1738, 2010.

B. Huber, R. Escudero, H. Busse, E. Seibold, H. C. Scholz et al., Description of Francisella hispaniensis sp. nov., isolated from human blood, reclassification of Francisella novicida (Larson et al. 1955) Olsufiev et al. 1959 as Francisella tularensis subsp. novicida comb. nov. and emended description of the genus Francisella, Int J Syst Evol Microbiol, vol.60, pp.1887-96, 2010.

A. Johansson, J. Celli, W. Conlan, K. L. Elkins, M. Forsman et al., Objections to the transfer of Francisella novicida to the subspecies rank of Francisella tularensis, Int J Syst Evol Microbiol, vol.60, pp.1717-1718, 2010.

D. G. Hollis, R. E. Weaver, A. G. Steigerwalt, J. D. Wenger, C. W. Moss et al., Francisella philomiragia comb. nov. (formerly Yersinia philomiragia) and Francisella tularensis biogroup novicida (formerly Francisella novicida) associated with human disease, J Clin Microbiol, vol.27, issue.7, pp.1601-1609, 1989.

L. Kreitmann, L. Terriou, D. Launay, Y. Caspar, R. Courcol et al., Disseminated Infection Caused by Francisella philomiragia, Emerg Infect Dis, vol.21, issue.12, pp.2260-2261, 2014.
DOI : 10.3201/eid2112.150615
URL : https://doi.org/10.3201/eid2112.150615

T. L. Mailman and M. H. Schmidt, Francisella philomiragia adenitis and pulmonary nodules in a child with chronic granulomatous disease, Can J Infect Dis Med Microbiol J Can Mal Infect Microbiol Médicale AMMI Can, vol.16, issue.4, pp.245-253, 2005.
DOI : 10.1155/2005/486417
URL : http://downloads.hindawi.com/journals/cjidmm/2005/486417.pdf

J. D. Wenger, D. G. Hollis, R. E. Weaver, C. N. Baker, G. R. Brown et al., Infection caused by Francisella philomiragia (formerly Yersinia philomiragia). A newly recognized human pathogen, Ann Intern Med, vol.110, issue.11, pp.888-92, 1989.
DOI : 10.7326/0003-4819-110-11-888

I. N. Ivanov, N. Mitkova, A. L. Reye, J. M. Hubschen, R. S. Vatcheva-dobrevska et al., Detection of New Francisella-Like Tick Endosymbionts in Hyalomma spp. and Rhipicephalus spp. (Acari: Ixodidae) from Bulgaria, Appl Environ Microbiol, vol.77, issue.15, pp.5562-5567, 2011.

K. F. Ottem, A. Nylund, E. Karlsbakk, A. Friis-møller, and T. Kamaishi, Elevation of Francisella philomiragia subsp. noatunensis Mikalsen et al. (2007) to Francisella noatunensis comb. nov. [syn. Francisella piscicida Ottem et al. (2008) syn. nov.] and characterization of Francisella noatunensis subsp. orientalis subsp. nov., two important fish pathogens, J Appl Microbiol, vol.106, issue.4, pp.1231-1274, 2009.

A. Sjödin, K. Svensson, M. Lindgren, M. Forsman, and P. Larsson, Whole-genome sequencing reveals distinct mutational patterns in closely related laboratory and naturally propagated Francisella tularensis strains, PloS One, vol.5, issue.7, p.11556, 2010.

K. Rydzewski, T. Schulz, E. Brzuszkiewicz, G. Holland, C. Lück et al., Genome sequence and phenotypic analysis of a first German Francisella sp. isolate (W12-1067) not belonging to the species Francisella tularensis, BMC Microbiol. 25 juin, vol.14, issue.1, p.169, 2014.

P. Keim, A. Johansson, and D. M. Wagner, Molecular epidemiology, evolution, and ecology of Francisella, Ann N Y Acad Sci, vol.1105, pp.30-66, 2007.

J. E. Staples, K. A. Kubota, L. G. Chalcraft, P. S. Mead, and J. M. Petersen, Epidemiologic and Molecular Analysis of Human Tularemia, Emerg Infect Dis, vol.12, issue.7, pp.1113-1121, 1964.

K. J. Kugeler, P. S. Mead, A. M. Janusz, J. E. Staples, K. A. Kubota et al., Molecular Epidemiology of Francisella tularensis in the United States, Clin Infect Dis, vol.48, issue.7, pp.863-70, 2009.

J. Farlow, K. L. Smith, J. Wong, M. Abrams, M. Lytle et al., Francisella tularensis Strain Typing Using Multiple-Locus, Variable-Number Tandem Repeat Analysis, J Clin Microbiol, vol.39, issue.9, pp.3186-92, 2001.

A. Johansson, J. Farlow, P. Larsson, M. Dukerich, E. Chambers et al., Worldwide Genetic Relationships among Francisella tularensis Isolates Determined by Multiple-Locus Variable-Number Tandem Repeat Analysis, J Bacteriol, vol.186, issue.17, pp.5808-5826, 2004.

A. J. Vogler, D. Birdsell, D. M. Wagner, and P. Keim, An optimized, multiplexed multi-locus variablenumber tandem repeat analysis system for genotyping Francisella tularensis, Lett Appl Microbiol, vol.48, issue.1, pp.140-144, 2009.

D. D. Duncan, A. J. Vogler, M. J. Wolcott, F. Li, D. S. Sarovich et al., Identification and typing of Francisella tularensis with a highly automated genotyping assay, Lett Appl Microbiol, vol.56, issue.2, pp.128-162, 2013.

K. Svensson, P. Larsson, D. Johansson, M. Byström, M. Forsman et al., Evolution of Subspecies of Francisella tularensis, J Bacteriol, vol.187, issue.11, pp.3903-3911, 2005.

M. Broekhuijsen, P. Larsson, A. Johansson, M. Bystrom, U. Eriksson et al., GenomeWide DNA Microarray Analysis of Francisella tularensis Strains Demonstrates Extensive Genetic Conservation within the Species but Identifies Regions That Are Unique to the Highly Virulent F. tularensis subsp. tularensis, J Clin Microbiol, vol.41, issue.7, pp.2924-2955, 2003.

K. Svensson, M. Granberg, L. Karlsson, V. Neubauerova, M. Forsman et al., A Real-Time PCR Array for Hierarchical Identification of Francisella Isolates, PLoS ONE, 2009.

M. Gyuranecz, D. N. Birdsell, W. Splettstoesser, E. Seibold, S. M. Beckstrom-sternberg et al., Phylogeography of Francisella tularensis subsp. holarctica, Europe. Emerg Infect Dis, vol.18, issue.2, pp.290-293, 2012.

G. A. Pandya, M. H. Holmes, J. M. Petersen, S. Pradhan, S. A. Karamycheva et al., Whole genome single nucleotide polymorphism based phylogeny of Francisella tularensis and its application to the development of a strain typing assay, BMC Microbiol, vol.9, issue.1, p.213, 2009.

A. Johansson and J. M. Petersen, Genotyping of Francisella tularensis, the causative agent of tularemia, J AOAC Int, vol.93, issue.6, pp.1930-1973, 2010.

D. N. Birdsell, A. Johansson, C. Öhrman, E. Kaufman, C. Molins et al., Francisella tularensis subsp. tularensis group A.I, United States, Emerg Infect Dis, vol.20, issue.5, pp.861-866, 2014.

G. Chanturia, D. N. Birdsell, M. Kekelidze, E. Zhgenti, G. Babuadze et al., Phylogeography of Francisella tularensis subspecies holarctica from the country of Georgia, BMC Microbiol, vol.11, p.139, 2011.

S. Kilic, D. N. Birdsell, A. Karagöz, B. Çelebi, Z. Bakkaloglu et al., Water as Source of Francisella tularensis Infection in Humans, Turkey. Emerg Infect Dis, vol.21, issue.12, pp.2213-2219, 2015.

P. Pilo, A. Johansson, and J. Frey, Identification of Francisella tularensis Cluster in Central and Western Europe, Emerg Infect Dis, vol.15, issue.12, pp.2049-51, 2009.

M. Maurin and M. Gyuranecz, Tularaemia: clinical aspects in Europe, Lancet Infect Dis, vol.16, issue.1, pp.113-137, 2016.

W. Muller, H. Hotzel, P. Otto, A. Karger, B. Bettin et al., German Francisella tularensis isolates from European brown hares (Lepus europaeus) reveal genetic and phenotypic diversity, BMC Microbiol, vol.13, p.61, 2013.

F. Origgi, J. Frey, and P. Pilo, Characterisation of a new group of Francisella tularensis subsp. holarctica in Switzerland with altered antimicrobial susceptibilities, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull, vol.19, issue.29, 1996.

M. P. Dempsey, M. Dobson, C. Zhang, M. Zhang, C. Lion et al., Genomic Deletion Marking an Emerging Subclone of Francisella tularensis subsp. holarctica in France and the Iberian Peninsula, Appl Environ Microbiol, vol.73, issue.22, pp.7465-70, 2007.

A. J. Vogler, D. N. Birdsell, J. Lee, J. Vaissaire, C. L. Doujet et al., Phylogeography of Francisella tularensis ssp. holarctica in France, Lett Appl Microbiol, vol.52, issue.2, pp.177-80, 2011.

G. Garrity, D. J. Brenner, N. R. Krieg, and J. R. Staley, Bergey's Manual of Systematic Bacteriology, The Proteobacteria, vol.2, 2005.

G. Sandström, A. Sjöstedt, M. Forsman, N. V. Pavlovich, and B. N. Mishankin, Characterization and classification of strains of Francisella tularensis isolated in the central Asian focus of the Soviet Union and in Japan, J Clin Microbiol, vol.30, issue.1, pp.172-177, 1992.

M. A. Apicella, D. Post, A. C. Fowler, B. D. Jones, J. A. Rasmussen et al., Identification, Characterization and Immunogenicity of an O-Antigen Capsular Polysaccharide of Francisella tularensis, PLoS ONE, 2010.

M. Mahawar, G. S. Kirimanjeswara, D. W. Metzger, and C. S. Bakshi, Contribution of Citrulline Ureidase to Francisella tularensis Strain Schu S4 Pathogenesis, J Bacteriol, vol.191, issue.15, pp.4798-806, 2009.

A. Tarnvik, WHO Guidelines on Tularaemia. Geneva: World Health Organization, 2007.

E. Jantzen, B. P. Berdal, and T. Omland, Cellular fatty acid composition of Francisella tularensis, J Clin Microbiol, vol.10, issue.6, pp.928-958, 1979.

N. J. Phillips, B. Schilling, M. K. Mclendon, M. A. Apicella, and B. W. Gibson, Novel Modification of Lipid A of Francisella tularensis, Infect Immun, vol.72, issue.9, pp.5340-5348, 2004.

B. D. Jones, M. Faron, J. A. Rasmussen, and J. R. Fletcher, Uncovering the components of the Francisella tularensis virulence stealth strategy. Front Cell Infect Microbiol, 2014.

D. Gury?ová, First isolation of Francisella tularensis subsp. tularensis in Europe, Eur J Epidemiol, vol.14, issue.8, pp.797-802, 1998.

S. M. Twine, H. Shen, J. F. Kelly, W. Chen, A. Sjostedt et al., Virulence comparison in mice of distinct isolates of type A Francisella tularensis, Microb Pathog, vol.40, issue.3, pp.133-141, 2006.

C. R. Molins, M. J. Delorey, B. M. Yockey, J. W. Young, S. W. Sheldon et al., Virulence Differences Among Francisella tularensis Subsp. tularensis Clades in Mice, PLoS ONE, 2010.

R. Hornick, Tularemia revisited, N Engl J Med, vol.345, issue.22, pp.1637-1646, 2001.

R. M. Jones, M. Nicas, A. Hubbard, M. D. Sylvester, and A. Reingold, The Infectious Dose of Francisella tularensis (Tularemia), Applied Biosafety, pp.227-266, 2005.

S. M. Beckstrom-sternberg, R. K. Auerbach, S. Godbole, J. V. Pearson, J. S. Beckstrom-sternberg et al., Complete genomic characterization of a pathogenic A.II strain of Francisella tularensis subspecies tularensis, PloS One, vol.2, issue.9, p.947, 2007.

E. Karlsson, K. Svensson, P. Lindgren, M. Byström, A. Sjödin et al., The phylogeographic pattern of Francisella tularensis in Sweden indicates a Scandinavian origin of Eurosiberian tularaemia, Environ Microbiol, vol.15, issue.2, pp.634-679, 2013.

W. Hesselbrock and L. Foshay, The Morphology of Bacterium tularense, J Bacteriol, vol.49, issue.3, pp.209-240, 1945.

H. T. Eigelsbach, W. Braun, and R. D. Herring, Studies on the variation of Bacterium tularense, J Bacteriol, vol.61, issue.5, pp.557-69, 1951.

C. R. Molins, M. J. Delorey, B. M. Yockey, J. W. Young, J. T. Belisle et al., Virulence difference between the prototypic Schu S4 strain (A1a) and Francisella tularensis A1a, A1b, A2 and type B strains in a murine model of infection, BMC Infect Dis, vol.14, p.67, 2014.

C. A. Forestal, M. Malik, S. V. Catlett, A. G. Savitt, J. L. Benach et al., Francisella tularensis Has a Significant Extracellular Phase in Infected Mice, J Infect Dis, vol.196, issue.1, pp.134-141, 2007.

M. Barel and A. Charbit, Francisella tularensis intracellular survival: to eat or to die, Microbes Infect, vol.15, pp.989-97, 2013.

A. Chong and J. Celli, The Francisella Intracellular Life Cycle: Toward Molecular Mechanisms of Intracellular Survival and Proliferation. Front Microbiol, 2010.

J. D. Hall, M. D. Woolard, B. M. Gunn, R. R. Craven, S. Taft-benz et al., Infected-Host-Cell Repertoire and Cellular Response in the Lung following Inhalation of Francisella tularensis Schu S4, LVS, or U112, Infect Immun, vol.76, issue.12, pp.5843-52, 2008.

J. Horzempa, D. M. O'dee, D. B. Stolz, J. M. Franks, D. Clay et al., Invasion of erythrocytes by Francisella tularensis, J Infect Dis, vol.204, issue.1, pp.51-60, 2011.

G. B. Moreau and B. J. Mann, Adherence and uptake of Francisella into host cells, Virulence, vol.4, issue.8, pp.826-858, 2013.

J. Pizarro-cerdá, A. Charbit, J. Enninga, F. Lafont, and P. Cossart, Manipulation of host membranes by the bacterial pathogens Listeria, Francisella, Shigella and Yersinia, Semin Cell Dev Biol, vol.60, pp.155-67, 2016.

D. L. Clemens and M. A. Horwitz, Uptake and intracellular fate of Francisella tularensis in human macrophages, Ann N Y Acad Sci, vol.1105, pp.160-86, 2007.

D. L. Clemens, B. Lee, and M. A. Horwitz, Francisella tularensis Enters Macrophages via a Novel Process Involving Pseudopod Loops, Infect Immun, vol.73, issue.9, pp.5892-902, 2005.

C. E. Bradburne, A. B. Verhoeven, G. C. Manyam, S. A. Chaudhry, E. L. Chang et al., Temporal Transcriptional Response during Infection of Type II Alveolar Epithelial Cells with Francisella tularensis Live Vaccine Strain (LVS) Supports a General Host Suppression and Bacterial Uptake by Macropinocytosis, J Biol Chem, vol.288, issue.15, pp.10780-91, 2013.

D. L. Clemens, P. Ge, B. Lee, M. A. Horwitz, and Z. H. Zhou, Atomic Structure of T6SS Reveals Interlaced Array Essential to Function, Cell, vol.160, issue.5, pp.940-51, 2015.

F. E. Nano and C. Schmerk, The Francisella Pathogenicity Island, Ann N Y Acad Sci, vol.1105, issue.1, pp.122-137, 2007.

K. Alkhuder, K. L. Meibom, I. Dubail, M. Dupuis, and A. Charbit, Glutathione provides a source of cysteine essential for intracellular multiplication of Francisella tularensis, PLoS Pathog, vol.5, issue.1, p.1000284, 2009.

S. Steele, L. Radlinski, S. Taft-benz, J. Brunton, and T. H. Kawula, Trogocytosis-associated cell to cell spread of intracellular bacterial pathogens, eLife, vol.5, p.10625, 2016.

A. Tularaemia and . Wildlife, , 2013.

, European Centre for Disease Prevention and Control. Annual epidemiological report 2014 -food-and waterborne diseases and zoonoses, 2014.

I. Lopes-de-carvalho, R. Escudero, C. Garcia-amil, H. Falcao, P. Anda et al., Francisella tularensis, Portugal. Emerg Infect Dis, vol.13, issue.4, pp.666-673, 2007.

J. M. Rijks, M. Kik, M. G. Koene, M. Y. Engelsma, P. Van-tulden et al., Tularaemia in a brown hare (Lepus europaeus) in 2013: first case in the Netherlands in 60 years, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull, vol.18, issue.49, 2013.

A. Hotta, O. Fujita, A. Uda, N. Sharma, K. Tanabayashi et al., In Vitro Antibiotic Susceptibility of Francisella tularensis Isolates from Japan, Jpn J Infect Dis, vol.66, issue.6, pp.534-540, 2013.

Y. Ohara, T. Sato, and M. Homma, Epidemiological analysis of tularemia in Japan (yato-byo), FEMS Immunol Med Microbiol, vol.13, issue.3, pp.185-194, 1996.

S. Gurcan, . Epidemiology, and . Tularemia, Balk Med J, vol.31, issue.1, pp.3-10, 2014.

K. W. Larssen, K. Bergh, B. T. Heier, L. Vold, and J. E. Afset, All-time high tularaemia incidence in Norway in 2011: report from the national surveillance, Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol, 2014.

Z. Cerný, Changes of the epidemiology and the clinical picture of tularemia in Southern Moravia (the Czech Republic) during the period 1936-1999, Eur J Epidemiol, vol.17, issue.7, pp.637-679, 2001.

L. Payne, M. Arneborn, A. Tegnell, and J. Giesecke, Endemic tularemia, Emerg Infect Dis, vol.11, issue.9, pp.1440-1442, 2003.

K. Svensson, E. Back, H. Eliasson, L. Berglund, M. Granberg et al., Landscape Epidemiology of Tularemia Outbreaks in Sweden, Emerg Infect Dis, vol.15, issue.12, pp.1937-1984, 2009.

A. Johansson, A. Lärkeryd, M. Widerström, S. Mörtberg, K. Myrtännäs et al., A respiratory tularemia outbreak caused by diverse clones of Francisella tularensis, 2014.

K. W. Larssen, J. E. Afset, B. T. Heier, T. Krogh, K. Handeland et al., Outbreak of tularaemia in central Norway, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull, issue.13, p.16, 2011.

I. Christova, T. Velinov, T. Kantardjiev, and A. Galev, Tularaemia outbreak in Bulgaria, Scand J Infect Dis, vol.36, pp.785-794, 2004.

T. Kantardjiev, I. Ivanov, T. Velinov, P. Padeshki, B. Popov et al., Tularemia outbreak, vol.12, issue.4, pp.678-80, 1997.

R. Reintjes, I. Dedushaj, A. Gjini, T. R. Jorgensen, B. Cotter et al., Tularemia outbreak investigation in Kosovo: case control and environmental studies, Emerg Infect Dis, vol.8, issue.1, pp.69-73, 2002.

A. M. Hauri, I. Hofstetter, E. Seibold, P. Kaysser, J. Eckert et al., Investigating an airborne tularemia outbreak, Germany. Emerg Infect Dis, vol.16, issue.2, pp.238-281, 2010.

J. L. Pérez-castrillón, P. Bachiller-luque, M. Martín-luquero, F. J. Mena-martín, and V. Herreros, Tularemia Epidemic in Northwestern Spain: Clinical Description and Therapeutic Response, Clin Infect Dis, vol.33, issue.4, pp.573-579, 2001.

S. Barut and I. Cetin, A tularemia outbreak in an extended family in Tokat Province, Turkey: observing the attack rate of tularemia, Int J Infect Dis, vol.13, issue.6, pp.745-753, 2009.

S. Helvaci, S. Gediko?lu, H. Akalin, and H. B. Oral, Tularemia in Bursa, Turkey: 205 cases in ten years, Eur J Epidemiol, vol.16, issue.3, pp.271-277, 2000.

Z. Mengeloglu, A. Duran, I. N. Hakyemez, T. Ocak, A. Kücükbayrak et al., Evaluation of patients with Tularemia in Bolu province in northwestern Anatolia, Turkey. J Infect Dev Ctries, vol.8, issue.3, pp.315-324, 2014.

H. Akal?n, S. Helvac?, and S. Gediko?lu, Re-emergence of tularemia in Turkey, Int J Infect Dis, vol.13, issue.5, pp.547-51, 2009.

G. Celebi, F. Baruönü, F. Ayo?lu, F. Cinar, A. Karadenizli et al., Tularemia, a reemerging disease in northwest Turkey: epidemiological investigation and evaluation of treatment responses, Jpn J Infect Dis, vol.59, issue.4, pp.229-263, 2006.

V. Siret, D. Barataud, M. Prat, V. Vaillant, S. Ansart et al., An outbreak of airborne tularaemia in France, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull, vol.11, issue.2, pp.58-60, 2004.

A. Mailles, N. Madani, M. Maurin, B. Garin-bastuji, and V. Vaillant, Unexpected increase of human and animal tularemia cases during winter, Médecine Mal Infect, vol.40, issue.5, pp.279-84, 2007.
URL : https://hal.archives-ouvertes.fr/hal-00993928

K. A. Feldman, R. E. Enscore, S. L. Lathrop, B. T. Matyas, M. Mcguill et al., An outbreak of primary pneumonic tularemia on Martha's Vineyard, N Engl J Med, vol.345, issue.22, pp.1601-1607, 2001.

J. M. Petersen, J. K. Carlson, G. Dietrich, R. J. Eisen, J. Coombs et al., Multiple Francisella tularensis Subspecies and Clades, Tularemia Outbreak, Emerg Infect Dis, vol.14, issue.12, pp.1928-1958, 2008.

Y. Wang, R. Hai, Z. Zhang, L. Xia, H. Cai et al., Genetic relationship between Francisella tularensis strains from China and from other countries, Biomed Environ Sci BES, vol.24, issue.3, pp.310-314, 2011.

J. Ariza-miguel, A. Johansson, M. I. Fernández-natal, C. Martínez-nistal, A. Orduña et al., Molecular investigation of tularemia outbreaks, Emerg Infect Dis, vol.20, issue.5, pp.754-61, 1997.

R. Grunow, A. Kalaveshi, A. Kühn, G. Mulliqi-osmani, and N. Ramadani, Surveillance of tularaemia in Kosovo, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull, vol.17, issue.28, 2001.

J. Capellan and I. W. Fong, Tularemia from a cat bite: case report and review of feline-associated tularemia, Clin Infect Dis Off Publ Infect Dis Soc Am, vol.16, issue.4, pp.472-477, 1993.

M. Gyuranecz, K. Rigó, A. Dán, G. Földvári, L. Makrai et al., Investigation of the ecology of Francisella tularensis during an inter-epizootic period, Vector Borne Zoonotic Dis Larchmt N, vol.11, issue.8, pp.1031-1036, 2011.

A. Kuehn, C. Schulze, P. Kutzer, C. Probst, A. Hlinak et al., Tularaemia seroprevalence of captured and wild animals in Germany: the fox (Vulpes vulpes) as a biological indicator, Epidemiol Infect, vol.141, issue.4, pp.833-873, 2013.

P. I. Padeshki, I. N. Ivanov, B. Popov, and T. V. Kantardjiev, The role of birds in dissemination of Francisella tularensis: first direct molecular evidence for bird-to-human transmission, Epidemiol Infect, vol.138, issue.3, pp.376-385, 2010.

H. Gehringer, E. Schacht, N. Maylaender, E. Zeman, P. Kaysser et al., Presence of an emerging subclone of Francisella tularensis holarctica in Ixodes ricinus ticks from southwestern Germany, Ticks Tick-Borne Dis, vol.4, issue.1-2, pp.93-100, 2013.

J. M. Petersen, P. S. Mead, and M. E. Schriefer, Francisella tularensis: an arthropod-borne pathogen, Vet Res, 2009.
URL : https://hal.archives-ouvertes.fr/hal-00903078

Z. Kreizinger, S. Hornok, A. Dan, S. Hresko, L. Makrai et al., Prevalence of Francisella tularensis and Francisella-Like Endosymbionts in the Tick Population of Hungary and the Genetic Variability of Francisella-Like Agents, Vector Borne Zoonotic Dis, vol.13, issue.3, pp.160-163, 2013.

J. Franke, J. Fritzsch, H. Tomaso, E. Straube, W. Dorn et al., Coexistence of pathogens in host-seeking and feeding ticks within a single natural habitat in Central Germany, Appl Environ Microbiol, vol.76, issue.20, pp.6829-6865, 2010.

S. M. Reese, J. M. Petersen, S. W. Sheldon, M. C. Dolan, G. Dietrich et al., Transmission efficiency of Francisella tularensis by adult american dog ticks (Acari: Ixodidae), J Med Entomol, vol.48, issue.4, pp.884-90, 2011.

V. Výrosteková, Transstadial transmission of Francisella tularensis by Ixodes ricinus ticks infected during the nymphal stage, Epidemiol Mikrobiol Imunol Cas Spolecnosti Epidemiol Mikrobiol Ceske Lek Spolecnosti JE Purkyne, vol.43, issue.4, pp.166-70, 1994.

M. Genchi, P. Prati, N. Vicari, A. Manfredini, L. Sacchi et al., Francisella tularensis: No Evidence for Transovarial Transmission in the Tularemia Tick Vectors Dermacentor reticulatus and Ixodes ricinus, PLoS ONE, 2015.

J. O. Lundstrom, A. Andersson, S. Backman, M. L. Schafer, M. Forsman et al., Transstadial Transmission of Francisella tularensis holarctica in Mosquitoes, Sweden. Emerg Infect Dis, vol.17, issue.5, pp.794-803, 2011.

J. Thelaus, A. Andersson, T. Broman, S. Backman, M. Granberg et al., Francisella tularensis Subspecies holarctica Occurs in Swedish Mosquitoes, Persists Through the Developmental Stages of Laboratory-Infected Mosquitoes and Is Transmissible During Blood Feeding, Microb Ecol, vol.67, pp.96-107, 2014.

T. Broman, J. Thelaus, A. Andersson, S. Backman, P. Wikstrom et al., Molecular Detection of Persistent Francisella tularensis Subspecies holarctica in Natural Waters, Int J Microbiol, 2011.

R. R. Parker, E. A. Steinhaus, G. M. Kohls, and W. L. Jellison, Contamination of natural waters and mud with Pasteurella tularensis and tularemia in beavers and muskrats in the northwestern United States, Bull Natl Inst Health US, vol.193, pp.1-161, 1951.

S. E. Gilbert and L. J. Rose, Survival and persistence of nonspore-forming biothreat agents in water, Lett Appl Microbiol, vol.55, issue.3, pp.189-94, 2012.

H. Forsman, . Larsson, and S. Johansson, Francisella tularensis does not manifest virulence in viable but non-culturable state, FEMS Microbiol Ecol, vol.31, issue.3, pp.217-241, 2000.

Z. L. Berrada and S. R. Telford, Survival of Francisella tularensis Type A in brackish-water, Arch Microbiol, vol.193, issue.3, pp.223-229, 2011.

H. Sim?ek, M. Taner, A. Karadenizli, M. Ertek, and H. Vahabo?lu, Identification of Francisella tularensis by both culture and real-time TaqMan PCR methods from environmental water specimens in outbreak areas where tularemia cases were not previously reported, Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol, vol.31, issue.9, pp.2353-2360, 2012.

H. Abd, T. Johansson, I. Golovliov, G. Sandström, and M. Forsman, Survival and growth of Francisella tularensis in Acanthamoeba castellanii, Appl Environ Microbiol, vol.69, issue.1, pp.600-606, 2003.

S. H. El-etr, J. J. Margolis, D. Monack, R. A. Robison, M. Cohen et al., Francisella tularensis type A strains cause the rapid encystment of Acanthamoeba castellanii and survive in amoebal cysts for three weeks postinfection, Appl Environ Microbiol, vol.75, issue.23, pp.7488-500, 2009.

C. Duncan, G. Krafsur, B. Podell, L. A. Baeten, I. Levan et al., Leptospirosis and tularaemia in raccoons, Zoonoses Public Health, vol.59, issue.1, pp.29-34, 2012.

D. D. Nelson, G. J. Haldorson, J. B. Stanton, S. M. Noh, D. S. Bradway et al., Francisella tularensis infection without lesions in gray tree squirrels (Sciurus griseus): a diagnostic challenge, J Vet Diagn Investig Off Publ Am Assoc Vet Lab Diagn Inc, vol.26, issue.2, pp.312-317, 2014.

H. Rossow, S. Sissonen, K. A. Koskela, P. M. Kinnunen, H. Hemmilä et al., Detection of Francisella tularensis in voles in Finland, Vector Borne Zoonotic Dis Larchmt N, vol.14, issue.3, pp.193-201, 2014.

U. Yilmaz, G. Gurcan, S. Ozkan, B. Karadenizli, and A. , Investigation of the presence of Francisella tularensis by culture, serology and molecular methods in mice of Thrace Region, Turkey. Mikrobiyoloji Bül, vol.48, issue.2, pp.213-235, 2014.

A. Decors, C. Lesage, E. Jourdain, P. Giraud, P. Houbron et al., Outbreak of tularaemia in brown hares (Lepus europaeus) in France, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull, issue.28, p.16, 2011.

S. B. Avashia, J. M. Petersen, C. M. Lindley, M. E. Schriefer, K. L. Gage et al., First reported prairie dog-to-human tularemia transmission, Emerg Infect Dis, vol.10, issue.3, pp.483-489, 2002.

C. M. Hansen, A. J. Vogler, P. Keim, D. M. Wagner, K. Hueffer et al., Acta Vet Scand, vol.53, issue.1, p.61, 1938.

W. C. Liles and R. J. Burger, Tularemia from domestic cats, West J Med, vol.158, issue.6, pp.619-641, 1993.

N. Chitadze, T. Kuchuloria, D. V. Clark, E. Tsertsvadze, M. Chokheli et al., Waterborne outbreak of oropharyngeal and glandular tularemia in Georgia: investigation and follow-up, Infection. déc, vol.37, issue.6, pp.514-535, 2009.

H. Erdem, D. Ozturk-engin, M. Yesilyurt, O. Karabay, N. Elaldi et al., Evaluation of tularaemia courses: a multicentre study from Turkey, Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis, 2014.

A. Mailles and V. Vaillant, 10 years of surveillance of human tularaemia in France, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull, vol.19, issue.45, p.20956, 2014.

C. A. Hanke, J. Otten, R. Berner, A. Serr, W. Splettstoesser et al., Ulceroglandular tularemia in a toddler in Germany after a mosquito bite, Eur J Pediatr, vol.168, issue.8, pp.937-977, 2009.

P. Ryden, R. Bjork, M. L. Schafer, J. O. Lundstrom, B. Petersen et al., Outbreaks of Tularemia in a Boreal Forest Region Depends on Mosquito Prevalence, J Infect Dis, vol.205, issue.2, pp.297-304, 2012.

K. E. Myrbäck, O. Ringertz, and S. Dahlstrand, An epidemic of tularemia in Sweden during the summer of 1967, Acta Pathol Microbiol Scand, vol.72, issue.3, pp.463-467, 1968.

H. Syrjälä, P. Kujala, V. Myllylä, and A. Salminen, Airborne transmission of tularemia in farmers, Scand J Infect Dis, vol.17, issue.4, pp.371-376, 1985.

S. M. Teutsch, W. J. Martone, E. W. Brink, M. E. Potter, G. Eliot et al., Pneumonic tularemia on Martha's Vineyard, N Engl J Med, vol.301, issue.15, pp.826-834, 1979.

, Centers for Disease Control and Prevention (CDC). Tularemia -Missouri, vol.58, issue.27, pp.744-752, 2000.

H. Eliasson and E. Bäck, Tularaemia in an emergent area in Sweden: an analysis of 234 cases in five years, Scand J Infect Dis, vol.39, issue.10, pp.880-889, 2007.

J. Fritzsch and W. D. Splettstoesser, Septic pneumonic tularaemia caused by Francisella tularensis subsp. holarctica biovar II, J Med Microbiol, vol.59, issue.9, pp.1123-1128, 2010.

J. R. Egan, I. M. Hall, and S. Leach, Modeling Inhalational Tularemia: Deliberate Release and Public Health Response, Biosecurity Bioterrorism Biodefense Strategy Pract Sci, vol.9, issue.4, pp.331-374, 2011.

B. Guerpillon, A. Boibieux, C. Guenne, C. Ploton, T. Ferry et al., Keep an Ear Out for Francisella tularensis: Otomastoiditis Cases after Canyoneering, 2016.

C. Akimana and Y. A. Kwaik, Francisella-Arthropod Vector Interaction and its Role in PathoAdaptation to Infect Mammals. Front Microbiol, 2011.

C. L. Carvalho, I. Lopes-de-carvalho, L. Zé-zé, M. S. Núncio, and E. L. Duarte, Tularaemia: A challenging zoonosis, Comp Immunol Microbiol Infect Dis, vol.37, issue.2, pp.85-96, 2014.

E. Gok, S. , K. Celikbas, A. Baykam, N. et al., Evaluation of tularemia cases focusing on the oculoglandular form, J Infect Dev Ctries, vol.8, issue.10, pp.1277-84, 2014.

C. Terrada, S. Azza, B. Bodaghi, L. Hoang, P. Drancourt et al., Rabbit hunter uveitis: case report of tularemia uveitis, BMC Ophthalmol, vol.16, issue.1, p.157, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01455619

S. Thompson, L. Omphroy, and T. Oetting, Parinaud's oculoglandular syndrome attributable to an encounter with a wild rabbit, Am J Ophthalmol, vol.131, issue.2, pp.283-287, 2001.

D. Aktas, B. Celebi, M. E. Isik, C. Tutus, H. Ozturk et al., Oropharyngeal Tularemia Outbreak Associated with Drinking Contaminated Tap Water, Turkey, Emerg Infect Dis, vol.21, issue.12, pp.2194-2200, 2013.

A. Karadenizli, M. Forsman, H. ?im?ek, M. Taner, C. Öhrman et al., Genomic analyses of Francisella tularensis strains confirm disease transmission from drinking water sources, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull, vol.20, issue.21, 2008.

A. Haholu, M. Saliho?lu, and V. Turhan, Granulomatous lymphadenitis can also be seen in tularemia, not only in tuberculosis, Int J Infect Dis, vol.17, issue.4, p.283, 2013.

B. Kandemir, I. Erayman, M. Bitirgen, E. T. Aribas, and S. Guler, Tularemia presenting with tonsillopharyngitis and cervical lymphadenitis: report of two cases, Scand J Infect Dis, vol.39, issue.6-7, pp.620-622, 2007.

A. Kaya, I. O. Uysal, A. S. Guven, A. Engin, A. Gulturk et al., Treatment failure of gentamicin in pediatric patients with oropharyngeal tularemia, Med Sci Monit Int Med J Exp Clin Res, vol.17, issue.7, pp.376-380, 2011.

R. Peter and T. Banyai, Erythema nodosum revealing oculoglandular tularemia, Dermatol Basel Switz, vol.202, issue.1, pp.79-80, 2001.

A. I. Ruiz, A. González, A. Miranda, V. Torrero, C. Gutiérrez et al., Sweet's syndrome associated with Francisella tularensis infection, Int J Dermatol, vol.40, issue.12, pp.791-794, 2001.

E. Senel, O. Sat?lm??, and B. Acar, Dermatologic manifestations of tularemia: a study of 151 cases in the mid-Anatolian region of Turkey, Int J Dermatol, 2014.

M. Barbaz, C. Piau, J. M. Tadie, I. Pelloux, S. Kayal et al., Rombencephalitis Caused by Francisella tularensis, J Clin Microbiol, vol.51, issue.10, pp.3454-3459, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00904614

L. Contentin, J. Soret, O. Zamfir, O. Gontier, T. Lherm et al., Francisella tularensis meningitis, Médecine Mal Infect, vol.41, issue.10, pp.556-564, 2011.

N. Gangat, Cerebral abscesses complicating tularemia meningitis, Scand J Infect Dis, vol.39, issue.3, pp.258-61, 2007.

D. M. Hofinger, L. Cardona, G. J. Mertz, and L. E. Davis, Tularemic meningitis in the United States, Arch Neurol, vol.66, issue.4, pp.523-530, 2009.

B. L. Rodgers, R. P. Duffield, T. Taylor, R. F. Jacobs, and G. E. Schutze, Tularemic meningitis, Pediatr Infect Dis J, vol.17, issue.5, pp.439-480, 1998.

M. Briere, A. Kaladji, F. Douane, J. P. Breux, P. Touroult-jupin et al., Infection, vol.44, issue.2, pp.263-268, 2016.

A. Tärnvik and M. C. Chu, New Approaches to Diagnosis and Therapy of Tularemia, Ann N Y Acad Sci, vol.1105, issue.1, pp.378-404, 2007.

L. Bevanger, J. A. Maeland, and A. I. Kvan, Comparative analysis of antibodies to Francisella tularensis antigens during the acute phase of tularemia and eight years later, Clin Diagn Lab Immunol, vol.1, issue.2, pp.238-278, 1994.

V. Chaignat, M. Djordjevic-spasic, A. Ruettger, P. Otto, D. Klimpel et al., Performance of seven serological assays for diagnosing tularemia, BMC Infect Dis, vol.14, issue.1, p.234, 2014.

J. M. Petersen, M. E. Schriefer, K. L. Gage, J. A. Montenieri, L. G. Carter et al., Methods for Enhanced Culture Recovery of Francisella tularensis, Appl Environ Microbiol, vol.70, issue.6, pp.3733-3738, 2004.

O. Karatuna, B. Çelebi, S. Can, I. Akyar, and S. Kiliç, The use of matrix-assisted laser desorption ionization-time of flight mass spectrometry in the identification of Francisella tularensis, Bosn J Basic Med Sci, vol.16, issue.2, pp.132-140, 2016.

E. Seibold, T. Maier, M. Kostrzewa, E. Zeman, and W. Splettstoesser, Identification of Francisella tularensis by Whole-Cell Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry: Fast, Reliable, Robust, and Cost-Effective Differentiation on Species and Subspecies Levels, J Clin Microbiol, vol.48, issue.4, pp.1061-1070, 2010.

E. Durighello, L. Bellanger, E. Ezan, and J. Armengaud, Proteogenomic biomarkers for identification of Francisella species and subspecies by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, Anal Chem, vol.86, pp.9394-9402, 2014.

M. Lundquist, M. B. Caspersen, P. Wikström, and M. Forsman, Discrimination of Francisella tularensis subspecies using surface enhanced laser desorption ionization mass spectrometry and multivariate data analysis, FEMS Microbiol Lett, vol.243, issue.1, pp.303-313, 2005.

E. Seibold, R. Bogumil, S. Vorderwülbecke, A. Dahouk, S. Buckendahl et al., Optimized application of surface-enhanced laser desorption/ionization time-of-flight MS to differentiate Francisella tularensis at the level of subspecies and individual strains, FEMS Immunol Med Microbiol, vol.49, issue.3, pp.364-73, 2007.

M. Forsman, G. Sandström, and A. Sjöstedt, Analysis of 16S Ribosomal DNA Sequences of Francisella Strains and Utilization for Determination of the Phylogeny of the Genus and for Identification of Strains by PCR, Int J Syst Bacteriol, vol.44, issue.1, pp.38-46, 1994.

L. Michelet, S. Bonnet, N. Madani, and S. Moutailler, Discriminating Francisella tularensis and Francisella-like endosymbionts in Dermacentor reticulatus ticks: Evaluation of current molecular techniques, Vet Microbiol, vol.163, issue.3-4, pp.399-403, 2013.

J. L. Versage, D. Severin, M. C. Chu, and J. M. Petersen, Development of a Multitarget Real-Time TaqMan PCR Assay for Enhanced Detection of Francisella tularensis in Complex Specimens, J Clin Microbiol, vol.41, issue.12, pp.5492-5501, 2003.

J. Ahlinder, C. Ohrman, K. Svensson, P. Lindgren, A. Johansson et al., Increased knowledge of Francisella genus diversity highlights the benefits of optimised DNA-based assays, BMC Microbiol, vol.12, p.220, 2012.

J. A. Higgins, Z. Hubalek, J. Halouzka, K. L. Elkins, A. Sjostedt et al., Detection of Francisella tularensis in infected mammals and vectors using a probe-based polymerase chain reaction, Am J Trop Med Hyg, vol.62, issue.2, pp.310-318, 2000.

A. Johansson, A. Ibrahim, I. Goransson, U. Eriksson, D. Gurycova et al., Evaluation of PCR-Based Methods for Discrimination of Francisella Species and Subspecies and Development of a Specific PCR That Distinguishes the Two Major Subspecies of Francisella tularensis, J Clin Microbiol, vol.38, issue.11, pp.4180-4185, 2000.

P. Larsson, K. Svensson, L. Karlsson, D. Guala, M. Granberg et al., Canonical InsertionDeletion Markers for Rapid DNA Typing of Francisella tularensis, Emerg Infect Dis, vol.13, issue.11, pp.1725-1757, 2007.

K. J. Kugeler, R. Pappert, Y. Zhou, and J. M. Petersen, Real-time PCR for Francisella tularensis types A and B. Emerg Infect Dis, vol.12, pp.1799-801, 2006.

D. N. Birdsell, A. J. Vogler, J. Buchhagen, C. A. Kaufman, E. Naumann et al., TaqMan Real-Time PCR Assays for Single-Nucleotide Polymorphisms Which Identify Francisella tularensis and Its Subspecies and Subpopulations, PloS One, vol.9, issue.9, p.107964, 2014.

P. Bossi, A. Tegnell, A. Baka, F. Van-loock, J. Hendriks et al., Bichat guidelines for the clinical management of tularaemia and bioterrorism-related tularaemia, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull, vol.9, issue.12, pp.9-10, 2004.

C. Dentan, P. Pavese, I. Pelloux, S. Boisset, J. Brion et al., Treatment of tularemia in pregnant woman, France. Emerg Infect Dis, vol.19, issue.6, pp.996-1004, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00965575

B. Gestin, E. Valade, F. Thibault, D. Schneider, and M. Maurin, Phenotypic and genetic characterization of macrolide resistance in Francisella tularensis subsp. holarctica biovar I, J Antimicrob Chemother, vol.65, issue.11, pp.2359-67, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00800681

C. J. Jaing, K. S. Mcloughlin, J. B. Thissen, A. Zemla, S. N. Gardner et al., Identification of Genome-Wide Mutations in Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next Generation Sequencing, PLoS ONE, 2016.

V. Sutera, M. Levert, W. P. Burmeister, D. Schneider, and M. Maurin, Evolution toward high-level fluoroquinolone resistance in Francisella species, J Antimicrob Chemother, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00961489

G. Enderlin, L. Morales, R. F. Jacobs, and J. T. Cross, Streptomycin and alternative agents for the treatment of tularemia: review of the literature, Clin Infect Dis Off Publ Infect Dis Soc Am, vol.19, issue.1, pp.42-49, 1994.

A. Ulu-kilic, G. Gulen, F. Sezen, S. Kilic, and I. Sencan, Tularemia in central Anatolia. Infection, vol.41, issue.2, pp.391-400, 2013.

I. B. Weber, G. Turabelidze, S. Patrick, K. S. Griffith, K. J. Kugeler et al., Clinical recognition and management of tularemia in Missouri: a retrospective records review of 121 cases, Clin Infect Dis Off Publ Infect Dis Soc Am, vol.55, issue.10, pp.1283-90, 2012.

A. Kaya, K. Deveci, I. O. Uysal, A. S. Güven, M. Demir et al., Tularemia in children: evaluation of clinical, laboratory and therapeutic features of 27 tularemia cases, Turk J Pediatr, vol.54, issue.2, pp.105-117, 2012.

M. Meric, A. Willke, E. Finke, R. Grunow, M. Sayan et al., Evaluation of clinical, laboratory, and therapeutic features of 145 tularemia cases: the role of quinolones in oropharyngeal tularemia, APMIS, vol.116, issue.1, pp.66-73, 2008.

A. Karakas, O. Coskun, C. Artuk, U. Savasci, H. C. Gul et al., Oropharyngeal tularemia cases admitted to a military hospital in Ankara, Turkey, J Infect Dev Ctries, vol.8, issue.8, pp.994-1003, 2014.

M. G. Gozel, A. Engin, E. E. Altuntas, I. Salk, A. Kaya et al., Evaluation of clinical and laboratory findings of pediatric and adult patients with oropharyngeal tularemia in Turkey: a combination of surgical drainage and antibiotic therapy increases treatment success, Jpn J Infect Dis, vol.67, issue.4, pp.295-304, 2014.

A. Kaya, I. Ö. Uysal, A. S. Güven, A. Engin, A. Gültürk et al., Treatment failure of gentamicin in pediatric patients with oropharyngeal tularemia, Med Sci Monit Int Med J Exp Clin Res, vol.17, issue.7, pp.376-380, 2011.

R. Komitova, R. Nenova, P. Padeshki, I. Ivanov, V. Popov et al., Tularemia in bulgaria 2003-2004, J Infect Dev Ctries, vol.4, issue.11, pp.689-94, 2010.

I. Sencan, I. Sahin, D. Kaya, S. Oksuz, D. Ozdemir et al., An Outbreak of Oropharyngeal Tularemia with Cervical Adenopathy Predominantly in the Left Side, Yonsei Med J, vol.50, issue.1, pp.50-54, 2009.

?. Gönen, A small outbreak of tularemia in a rural area, Turk J Med Sci, vol.43, issue.1, pp.75-83, 2013.

M. S. Tezer, G. Övet, N. Alata?, M. H. Görgülü, E. Koç et al., Clinical manifestations of 16 oropharyngeal tularemia patients: experience of a referral hospital in the city of Konya, Turkey, Turk J Med Sci, vol.43, issue.2, pp.227-258, 2013.

S. Ca?l?, A. Vural, O. Sönmez, I. Yüce, and E. Güney, Tularemia: a rare cause of neck mass, evaluation of 33 patients, Eur Arch Oto-Rhino-Laryngol Off J Eur Fed Oto-Rhino-Laryngol Soc EUFOS Affil Ger Soc Oto-Rhino-Laryngol -Head Neck Surg, vol.268, issue.12, pp.1699-704, 2011.

S. Celebi, M. Hacimustafaoglu, and S. Gedikoglu, Tularemia in children, Indian J Pediatr, vol.75, issue.11, pp.1129-1161, 2008.

U. Jounio, M. Renko, and M. Uhari, An outbreak of holarctica-type tularemia in pediatric patients, Pediatr Infect Dis J, vol.29, issue.2, pp.160-162, 2010.

J. Snowden and S. Stovall, Tularemia: retrospective review of 10 years' experience in Arkansas, Clin Pediatr (Phila), vol.50, issue.1, pp.64-72, 2011.

Z. Bicakci and M. Parlak, A neglected cause of cervical lymphadenitis. Oropharyngeal tularemia, Saudi Med J, vol.29, issue.7, pp.1059-61, 2008.

J. T. Cross, G. E. Schutze, and R. F. Jacobs, Treatment of tularemia with gentamicin in pediatric patients, Pediatr Infect Dis J, vol.14, issue.2, pp.151-153, 1995.

F. Oz, A. Eksioglu, G. Tan?r, G. Bayhan, O. Metin et al., Evaluation of clinical and sonographic features in 55 children with tularemia, Vector Borne Zoonotic Dis Larchmt N, vol.14, issue.8, pp.571-576, 2014.

H. Tezer, A. Ozkaya-parlakay, H. Aykan, M. Erkocoglu, B. Gülhan et al., Tularemia in Children, vol.21, issue.1, pp.1-7, 2009.

A. Johansson, L. Berglund, L. Gothefors, A. Sjöstedt, and A. Tärnvik, Ciprofloxacin for treatment of tularemia in children, Pediatr Infect Dis J, vol.19, issue.5, pp.449-53, 2000.

E. Georgi, E. Schacht, H. C. Scholz, and W. D. Splettstoesser, Standardized broth microdilution antimicrobial susceptibility testing of Francisella tularensis subsp. holarctica strains from Europe and rare Francisella species, J Antimicrob Chemother, vol.67, issue.10, pp.2429-2462, 2012.

L. Shadoud, I. Almahmoud, S. Jarraud, E. J. Larrat, S. Schwebel et al., Hidden Selection of Bacterial Resistance to Fluoroquinolones In Vivo: The Case of Legionella pneumophila and Humans, EBioMedicine, vol.2, issue.9, pp.1179-85, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01980608

D. I. Andersson and D. Hughes, Antibiotic resistance and its cost: is it possible to reverse resistance?, Nat Rev Microbiol, vol.8, issue.4, pp.260-71, 2010.

A. Fàbrega, S. Madurga, E. Giralt, and J. Vila, Mechanism of action of and resistance to quinolones, Microb Biotechnol, vol.2, issue.1, pp.40-61, 2009.

L. Scola, B. Elkarkouri, K. Li, W. Wahab, T. Fournous et al., Rapid comparative genomic analysis for clinical microbiology: The Francisella tularensis paradigm, Genome Res, vol.18, issue.5, pp.742-50, 2008.

B. M. Loveless, A. Yermakova, D. R. Christensen, J. P. Kondig, I. Heine et al., Identification of ciprofloxacin resistance by SimpleProbe TM , High Resolution Melt and Pyrosequencing TM nucleic acid analysis in biothreat agents: Bacillus anthracis, Yersinia pestis and Francisella tularensis, Mol Cell Probes, vol.24, issue.3, pp.154-60, 2010.

Y. Caspar, Évaluation de l'activité antibactérienne de nouveaux composés bis-indoliques de synthèse, de structure proche de celles d'alcaloïdes d'origine marine

X. Guinchard, Y. Vallée, and J. Denis, Total Syntheses of Brominated Marine Sponge Alkaloids, Org Lett, vol.9, pp.3761-3765, 2007.

X. Guinchard, Y. Vallée, and J. Denis, Total Synthesis of Marine Sponge Bis(indole) Alkaloids of the Topsentin Class, J Org Chem, vol.72, issue.10, pp.3972-3977, 2007.

J. Denis, C. Jolivalt, M. Maurin, and M. Jeanty, Bis-Indolic Derivatives, a Process for Preparing the Same and Their Uses as a Drug, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00801251

J. Denis, C. Jolivalt, M. Maurin, and O. Burchak, Bis-Indolic Derivatives, Their Uses in Particular as Antibacterials. WO, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00801260

D. , G. Moreau-née, L. , N. Vallee, Y. Novel et al., , 2008.

A. Harms, E. Maisonneuve, and K. Gerdes, Mechanisms of bacterial persistence during stress and antibiotic exposure, Science, vol.354, issue.6318, p.4268, 2016.

M. L. Van-hoek, Biofilms. Virulence, 2013.

, R1 : 4 x 10 ml (lyophilisé) R2 : 4 x 10 ml de solvant 1 notice fournie dans le coffret ou téléchargeable sur

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. .. Chlorhydrate-de-cystéine,

J. E. Martin, . E. Billing-t, and J. F. Hackney, Primary isolation of N. gonorrhoeae with a new commercial medium -Publ, Health. Rep, vol.82, pp.361-363, 1967.

J. D. Thayer and J. E. Martin, Improved medium selective for cultivation of N. gonorrhoeae and N. meningitidisPubl, Health. Rep, vol.81, pp.559-562, 1966.

. T. Evangelista-a and . H. Beilstein-r, Laboratory diagnosis of Gonorrhea, 1993.

, La sous espèce la plus virulente, F. tularensis subsp. tularensis, est retrouvée uniquement en Amérique du Nord, alors que la sous-espèce F. tularensis subsp. holarctica est présente dans tout l'hémisphère Nord. En France toutes les souches appartiennent au biovar I de la sous-espèce holarctica et plus précisément au groupe phylogénétique B.FTNF002-00. Bien que rarement grave en France, la tularémie pose le problème de taux d'échecs thérapeutiques élevés, jusqu'à 25% en cas de traitement par ciprofloxacine ou gentamicine, et 35% pour la doxycycline, Résumé La tularémie est une zoonose liée à la bactérie Francisella tularensis, hautement pathogène pour l'homme

, Les fluoroquinolones (en particulier la ciprofloxacine et la lévofloxacine) présentent concentrations minimales inhibitrices les plus basses, devant la gentamicine et la doxycycline. Les données disponibles in vitro et en modèle animal étant corrélées aux données humaines en termes d'efficacité et de taux d'échecs thérapeutiques, il semble néanmoins préférable de positionner la ciprofloxacine en première ligne pour le traitement des formes modérées de tularémie et de limiter l, L'analyse de la littérature ainsi que la détermination de la sensibilité de 59 souches françaises de F. tularensis subsp. holarctica à 18 antibiotiques

, La sélection in vitro de souches résistantes aux fluoroquinolones est possible, ce qui suggère la possibilité d'émergence de mutants résistants in vivo pour expliquer les taux d'échec thérapeutiques. Les principales mutations de résistance aux fluoroquinolones chez F. tularensis sont observées au niveau des gènes gyrA et gyrB codant pour les topoisomérases de type II. L'impact fonctionnel de mutations de résistances aux fluoroquinolones a été caractérisé in vitro chez F. novicida, pris comme modèle de bactérie avirulente proche de F. tularensis. L'activité de superenroulement et de clivage de l'ADN en présence de fluoroquinolones a été déterminée suite à la reconstruction in vitro de complexes GyrA/GyrB fonctionnels. La résistance aux fluoroquinolones était la plus forte en cas de mutation D87G/D87Y pour la sous-unité GyrA ou +P466 pour la sous-unité GyrB. La mutation P43H située en dehors du QRDR de GyrA est à l'origine d'un plus faible niveau de résistance. La mutation D487R-?K488 en dehors du QRDR de GyrB ne confère pas de résistance intrinsèque mais potentialise l'effet d'une mutation D87G concomitante. En revanche, l'identification de mutations de résistance in vivo au sein des QRDR des gènes gyrA et gyrB chez des patients en situation d'échec thérapeutique traités par une fluoroquinolone est demeurée négative. Enfin, notre recherche a permis d'identifier de nouveaux composés de synthèse de structure bis-indolique possédant des activités antibactériennes. Ces composés sont bactériostatiques vis-à-vis de F. tularensis mais bactéricides vis-à-vis des staphylocoques y compris vis-à-vis de souches multi-résistantes de Staphylococcus aureus avec des CMI90 évaluées à 2mg/L chez F, L'azithromycine et la télithromycine ont été identifiées comme des alternatives thérapeutiques envisageables en cas d'infection par une souche de biovar I de F. tularensis subsp. holarctica lorsqu'existe une contre-indication aux traitements de première ligne. Des études en modèles animaux restent néanmoins nécessaires pour conforter ces dernières observations

, Mots Clés : Nouvelles stratégies thérapeutiques, Francisella tularensis, Composés bis-indoliques