Antibacterial spectrum of a tetrazole-based reversible inhibitor of serine β-lactamases.

Antibacterial spectrum of a tetrazole-based reversible inhibitor of serine β-lactamases.
Antimicrob Agents Chemother. 2018 May 29;:
Authors: Pemberton OA, Zhang X, Nichols DA, DeFrees K, Jaishankar P, Bonnet R, Adams J, Shaw LN, Renslo AR, Chen Y
Abstract
CTX-M is the most prevalent family of extended-spectrum β-lactamases. We recently developed a tetrazole-derived non-covalent inhibitor of CTX-M-9. Here, we present biochemical and microbiological activity of this inhibitor across a representative panel of serine β-lactamases and Gram-negative bacteria. The compound displayed significant activity against all major subgroups of CTX-M, including CTX-M-15, while exhibiting some low-level inhibition of other serine β-lactamases. Complex crystal structures with CTX-M-14 S237A mutant and CTX-M-27 illustrate the binding contribution of specific active site residues on the β3 strand. In vitro pharmacokinetic studies revealed drug-like properties and positive prospects for further optimization. These studies suggest that tetrazole-based compounds can provide novel chemotypes for future serine β-lactamase inhibitor discovery.
PMID: 29844038 [PubMed - as supplied by publisher]

Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Pemberton OA, Zhang X, Nichols DA, DeFrees K, Jaishankar P, Bonnet R, Adams J, Shaw LN, Renslo AR, Chen Y Tags: Antimicrob Agents Chemother Source Type: research