Mycobacterium abscessus L,D-transpeptidases are susceptible to inactivation by carbapenems and cephalosporins but not penicillins

As a growing number of clinical isolates of Mycobacterium abscessus are resistant to most antibiotics, new treatment options that are effective against these drug-resistant strains are desperately needed. The majority of the linkages in the cell wall peptidoglycan of M. abscessus are synthesized by nonclassical transpeptidases, namely, the L,D-transpeptidases. Emerging evidence suggests that these enzymes represent a new molecular vulnerability in this pathogen. Recent studies have demonstrated that inhibition of these enzymes by the carbapenem class of -lactams determines their activity against Mycobacterium tuberculosis. Here, we studied the interactions of -lactams with two L,D-transpeptidases in M. abscessus, namely, Ldt_Mab1 and Ldt_Mab2, and found that both the carbapenem and cephalosporin, but not penicillin, subclasses of -lactams inhibit these enzymes. Contrary to the commonly held belief that combination therapy with -lactams is redundant, doripenem and cefdinir exhibit synergy against both pansusceptible M. abscessus and clinical isolates that are resistant to most antibiotics, which suggests that dual--lactam therapy has potential for the treatment of M. abscessus. Finally, we solved the first crystal structure of an M. abscessus L,D-transpeptidase, Ldt_Mab2, and using substitutions of critical amino acids in the catalytic site and computational simulations, we describe the key molecular interactions between this enzyme and -lactams, which provide an insight into the molecular basis for the relative efficacy of different β-lactams against M. abscessus.