Atypically Modified Carbapenem Antibiotics Display Improved Antimycobacterial Activity in the Absence of β-Lactamase Inhibitors.

Commercial carbapenem antibiotics are being used to treat multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis. Like other β-lactams, carbapenems are irreversible inhibitors of serine d,d-transpeptidases involved in peptidoglycan biosynthesis. In addition to d,d-transpeptidases, mycobacteria also utilize nonhomologous cysteine l,d-transpeptidases (Ldts) to cross-link the stem peptides of peptidoglycan, and carbapenems form long-lived acyl-enzymes with Ldts. Commercial carbapenems are C2 modifications of a common scaffold. This study describes the synthesis of a series of atypical, C5α modifications of the carbapenem scaffold, microbiological evaluation against () and the nontuberculous mycobacterial species, (), as well as acylation of an important mycobacterial target Ldt, Ldt. evaluation of these C5α-modified carbapenems revealed compounds with standalone (, in the absence of a β-lactamase inhibitor) minimum inhibitory concentrations (MICs) superior to meropenem-clavulanate for , and meropenem-avibactam for . Time-kill kinetics assays showed better killing (2-4 log decrease) of and with lower concentrations of compound as compared to meropenem. Although susceptibility of clinical isolates to meropenem varied by nearly 100-fold, maintained excellent activity against all and strains. High resolution mass spectrometry revealed that acylates Ldt at a rate comparable to meropenem, but subsequently undergoes an unprecedented carbapenem fragmentation, leading to an acyl-enzyme with mass of Δ = +86 Da. Rationale for the divergence of the nonhydrolytic fragmentation of the Ldt acyl-enzymes is proposed. The observed activity illustrates the potential of novel atypical carbapenems as prospective candidates for treatment of and infections.