Modified penicillin molecule with carbapenem-like stereochemistry specifically inhibits Class C {beta}-lactamases [PublishAheadOfPrint]

Bacterial β-lactamases readily inactivate most penicillins and cephalosporins by hydrolyzing and "opening" their signature β-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based Class A, C and D β-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule MPC-1 by "grafting" carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C5 and C6 instead of cis, and a 6-α hydroxyethyl moiety to replace the original 6-β aminoacyl group. MPC-1 selectively inhibits Class C β-lactamase such as P99 by forming a non-hydrolyzable acyl adduct and its inhibitory potency is ~2-5 times higher than that for clinically used β-lactamase inhibitors clavulanate and sulbactam. Crystal structure of MPC-1 forming acyl adduct with P99 reveals a novel binding mode for MPC-1 that resembles carbapenem bound in the active site of Class A β-lactamase. Furthermore, in this novel binding mode, the carboxyl group of MPC-1 blocks the deacylation reaction by occluding the critical catalytic water molecule and renders the acyl adduct non-hydrolyzable. Our results suggest that, by incorporating carbapenem-like stereochemistry, the current collection of over 100 penicillins and cephalosporins can be modified into candidate compounds for development of novel β-lactamase inhibitors.

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