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

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

SUBMITTER: Eidam O 

PROVIDER: S-EPMC3491531 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature