Competing off-loading mechanisms of meropenem from an l,d -transpeptidase reduce antibiotic effectiveness

Significance Meropenem is a broad-spectrum carbapenem antibiotic widely used in the clinic. Its inhibition ofl,d -transpeptidase cell-wall biosynthetic enzymes is increasingly recognized as a critical aspect of its broad-spectrum activity, particularly against mycobacterial species includingMycobacterium tuberculosis . We have demonstrated unexpected, reversible, and nonhydrolytic off-loading reactions of meropenem with one of its key targets, LdtMt2 , representative of thel,d -transpeptidase superfamily. These findings belie the tacit assumption of irreversible inhibition with an exclusively hydrolytic off mechanism for carbapenems against their classical target, the penicillin-binding proteins. While modestly effective against tuberculosis, existing carbapenems have not been optimized for potency againstl,d -transpeptidases. The knowledge gained here of two nonhydrolytic off-loading mechanisms provides important insights to help guide the design and synthesis of improved carbapenems.