Insights into the L,D-Transpeptidases and D,D-Carboxypeptidase of Mycobacterium abscessus: Ceftaroline, Imipenem, and Novel Diazabicyclooctane Inhibitors

Mycobacterium abscessus is a highly drug-resistant nontuberculous mycobacterium (NTM). Efforts to discover new treatments for M. abscessus infections are accelerating, with a focus on cell wall synthesis proteins (M. abscessus L,D-transpeptidases 1 to 5 [Ldt(Mab1) to Ldt(Mab5)] and D,D-carboxypeptidase) that are targeted by beta-lactam antibiotics. A challenge to this approach is the presence of chromosomally encoded beta-lactamase (Bla(Mab)). Using a mechanism-based approach, we found that a novel ceftaroline-imipenem combination effectively lowered the MICs of M. abscessus isolates (MIC50 = 8 angstrom for ceftaroline to enter. Our analysis demonstrates that ceftaroline and imipenem binding to multiple targets (L,D-transpeptidases and D,D-carboxypeptidase) and provides a mechanistic rationale for the effectiveness of this dual beta-lactam combination in M. abscessus infections.