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Fragment-guided design of subnanomolar beta-lactamase inhibitors active in vivo

Abstract : Fragment-based design was used to guide derivatization of a lead series of beta-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K-i of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with beta-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime: 5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome beta-lactamase-based resistance, a key clinical challenge.
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Oliv Eidam, Chiara Romagnoli, Guillaume Dalmasso, Sarah Barelier, Emilia Caselli, et al.. Fragment-guided design of subnanomolar beta-lactamase inhibitors active in vivo. Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2012, 109 (43), pp.17448 - 17453. ⟨10.1073/pnas.1208337109⟩. ⟨hal-02650778⟩



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