Figure 6.

Fragments guide lead derivatization of β-lactamase inhibitors. (A) Lead compound 24 (dark grey) was successfully modified to 25 (light grey) to pick up an extra hydrogen bond with residue G320 of E. coli AmpC, inspired by a fragment (orange) binding pose (figures prepared using structures deposited with PDB codes 3O87,⁹⁴ 2HDR,¹⁰⁷ and 4E3I,⁹⁵ for binding poses of 24, the carboxylate fragment, and 25, respectively). (B) The same interactions are made by 26 (light grey), modified to incorporate a tetrazole moiety, as suggested by another fragment (magenta) (figures prepared using structures deposited with PDB codes 3O87, 3GR2,¹⁰⁸ and 4E3J,⁹⁵ for binding poses of 24, the tetrazole fragment, and 26, respectively). Hydrogen bonds are shown as dashed yellow lines. AmpC = fold reduction in MIC of cefotaxime against a strain of E. coli overexpressing class C β-lactamase AmpC, when the compound was added at a 1:4 ratio of cefotaxime to β-lactamase inhibitor; CTX-M = fold reduction in MIC of cefotaxime against a strain of E. coli overexpressing class A β-lactamase CTX-M-14, when the compound was added at a 1:4 ratio of cefotaxime to β-lactamase inhibitor.