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As a growing number of clinical isolates ofMycobacterium 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 ofM. abscessus are synthesized by nonclassical transpeptidases, namely, thel ,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 againstMycobacterium tuberculosis . Here, we studied the interactions of β-lactams with twol ,d -transpeptidases inM. abscessus , namely, LdtMab1 and LdtMab2 , and found that both the carbapenem and cephalosporin, but not penicillin, subclasses 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 pansusceptibleM. abscessus and clinical isolates that are resistant to most antibiotics, which suggests that dual-β-lactam therapy has potential for the treatment ofM. abscessus . Finally, we solved the first crystal structure of anM. abscessus l ,d -transpeptidase, LdtMab2 , 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 againstM. abscessus .

antimicrobial agents and chemotherapy

Mycobacterium abscessus <scp>l</scp> , <scp>d</scp> -Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins

Mycobacterium abscessus l , d -Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins