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

Pankaj Kumar, Varsha Chauhan, José Rogério A. Silva, Jerônimo Lameira, Felipe B. D’Andrea, Shao Gang Li, Stephan L. Ginell, Joel S. Freundlich, Cláudio Nahum Alves, Scott Bailey, Keira A. Cohen, Gyanu Lamichhane

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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 -lactams determines their activity against Mycobacterium tuberculosis. Here, we studied the interactions of -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 -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, 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 -lactams, which provide an insight into the molecular basis for the relative efficacy of different β-lactams against M. abscessus.

Original languageEnglish (US)
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number10
DOIs
StatePublished - 2017

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Keywords

  • Beta-lactams
  • Carbapenem
  • Cephalosporin
  • L,D-transpeptidase
  • Mycobacterium abscessus

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