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Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17448-53. doi: 10.1073/pnas.1208337109. Epub 2012 Oct 5.

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo.

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Department of Pharmaceutical Chemistry, University of California, 1700 Fourth Street, Byers Hall, San Francisco, CA 94158, USA.


Fragment-based design was used to guide derivatization of a lead series of β-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 β-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 β-lactamase-based resistance, a key clinical challenge.

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