Resistance of the complex to fosmidomycin and fosmidomycin derivatives

Anne-Sophie Messiaen (1) , Thomas Verbrugghen (1) , Charlotte Declerck (1) , Regina Ortmann (2) , Martin Schlitzer (2) , Hans Nelis (1) , Serge van Calenbergh (1) , Tom Coenye (1)

1 UGENT - Universiteit Gent = Ghent University
2 Department of Pharmaceutical Chemistry

The complex (BCC) is a group of 17 closely related opportunistic pathogens that are able to infect the respiratory tract of cystic fibrosis patients. BCC bacteria are intrinsically resistant to many antibiotics and are therefore difficult to eradicate. Fosmidomycin could be a new therapeutic agent to treat BCC infections as it inhibits 1-deoxy--xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in the non-mevalonate pathway essential in BCC bacteria for isoprenoid synthesis. In this study, the antimicrobial activity of fosmidomycin and eight fosmidomycin derivatives towards 40 BCC strains was investigated. All BCC strains were resistant to fosmidomycin, although addition of glucose-6-phosphate reduced the minimum inhibitory concentrations values of FR900098, the fosmidomycin acetyl derivative, from 512mg/L to 64mg/L for and . This enhanced activity was linked to increased expression of the genes involved in glycerol-3-phosphate transport, which appears to be the only route for fosmidomycin import in BCC bacteria. Furthermore, upregulation of a fosmidomycin resistance gene () encoding an efflux pump was observed during fosmidomycin and FR900098 treatment. These results strongly suggest that the observed resistance in BCC bacteria is due to insufficient uptake accompanied by fosmidomycin and FR900098 efflux.

Mots clés: CC; Fosmidomycin; FR900098; Tolerance; Glucose-6-phosphate; fsr

Domaines: Microbiologie et Parasitologie

Anne-Sophie Messiaen, Thomas Verbrugghen, Charlotte Declerck, Regina Ortmann, Martin Schlitzer, et al.. Resistance of the complex to fosmidomycin and fosmidomycin derivatives. International Journal of Antimicrobial Agents, 2011, ⟨10.1016/j.ijantimicag.2011.04.020⟩. ⟨hal-00722869⟩