Antibacterial spectrum of a tetrazole-based reversible inhibitor of serine {beta}-lactamases [PublishAheadOfPrint]

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.

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