Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine beta-Lactamases.
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Pemberton OA, Zhang X, Nichols DA, DeFrees K, Jaishankar P, Bonnet R, Adams J, Shaw LN, Renslo AR, Chen Y
Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine beta-Lactamases.
Antimicrob Agents Chemother. 2018 Jul 27;62(8). pii: AAC.02563-17. doi: 10.1128/AAC.02563-17. Print 2018 Aug.
- PubMed ID
- 29844038 [ View in PubMed]
- Abstract
CTX-M is the most prevalent family of extended-spectrum beta-lactamases. We recently developed a tetrazole-derived noncovalent inhibitor of CTX-M-9. Here, we present the biochemical and microbiological activity of this inhibitor across a representative panel of serine beta-lactamases and Gram-negative bacteria. The compound displayed significant activity against all major subgroups of CTX-M, including CTX-M-15, while it exhibited some low-level inhibition of other serine beta-lactamases. Complex crystal structures with the CTX-M-14 S237A mutant and CTX-M-27 illustrate the binding contribution of specific active-site residues on the beta3 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 beta-lactamase inhibitor discovery.