Mycobacterium abscessus l,d-Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins.
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Kumar P, Chauhan V, Silva JRA, Lameira J, d'Andrea FB, Li SG, Ginell SL, Freundlich JS, Alves CN, Bailey S, Cohen KA, Lamichhane G
Mycobacterium abscessus l,d-Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins.
Antimicrob Agents Chemother. 2017 Sep 22;61(10). pii: AAC.00866-17. doi: 10.1128/AAC.00866-17. Print 2017 Oct.
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- 28760902 [ View in PubMed]
- Abstract
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 beta-lactams determines their activity against Mycobacterium tuberculosis Here, we studied the interactions of beta-lactams with two l,d-transpeptidases in M. abscessus, namely, LdtMab1 and LdtMab2, and found that both the carbapenem and cephalosporin, but not penicillin, subclasses of beta-lactams inhibit these enzymes. Contrary to the commonly held belief that combination therapy with beta-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-beta-lactam therapy has potential for the treatment of M. abscessus Finally, we solved the first crystal structure of an M. 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 beta-lactams, which provide an insight into the molecular basis for the relative efficacy of different beta-lactams against M. abscessus.