title: Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, 1700 Fourth Street, Byers Hall, San Francisco, CA 94158, USA.
authors.forename: Oliv
authors.initials: O
authors.lastname: Eidam
authors.forename: Chiara
authors.initials: C
authors.lastname: Romagnoli
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dalmasso
authors.forename: Sarah
authors.initials: S
authors.lastname: Barelier
authors.forename: Emilia
authors.initials: E
authors.lastname: Caselli
authors.forename: Richard
authors.initials: R
authors.lastname: Bonnet
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.forename: Fabio
authors.initials: F
authors.lastname: Prati
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D014961:X-Ray Diffraction; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors