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Publication Abstract from PubMed

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 beta-lactams determines their activity against M. tuberculosis Here, we studied the interactions of beta-lactams with two L,D-transpeptidases in M. abscessus, namely LdtMab1 and LdtMab2, and found both the carbapenem and cephalosporin--but not penicillin-sub-class 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 pan-susceptible M. abscessus and clinical isolates that are resistant to most antibiotics, which suggests that dual-beta-lactam therapy holds potential for treatment of M. abscessus Lastly, 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.

Mycobacterium abscessus L,D-transpeptidases are susceptible to inactivation by carbapenems and cephalosporins but not penicillins.,Kumar P, Chauhan V, Silva JRA, Lameira J, d'Andrea F, Li S, Ginell SL, Freundlich JS, Alves CN, Bailey S, Cohen KA, Lamichhane G Antimicrob Agents Chemother. 2017 Jul 31. pii: AAC.00866-17. doi:, 10.1128/AAC.00866-17. PMID:28760902^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.