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

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 non-classical 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 β-lactams determines their activity against M. tuberculosis. Here, we studied the interactions of β-lactams with two L,D-transpeptidases in M. abscessus, namely Ldt_Mab1 and Ldt_Mab2, and found both the carbapenem and cephalosporin—-but not penicillin—sub-class of β-lactams inhibit these enzymes. Contrary to the commonly held belief that combination therapy with β-lactams is redundant, doripenem and cefdinir exhibit synergy against both pan-susceptible M. abscessus and clinical isolates that are resistant to most antibiotics, which suggests that dual-β-lactam therapy holds potential for treatment of M. abscessus. Lastly, 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 β-lactams, which provide an insight into the molecular basis for the relative efficacy of different β-lactams against M. abscessus.

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