TY - JOUR
T1 - Mycobacterium abscessus L,D-transpeptidases are susceptible to inactivation by carbapenems and cephalosporins but not penicillins
AU - Kumar, Pankaj
AU - Chauhan, Varsha
AU - Silva, José Rogério A.
AU - Lameira, Jerônimo
AU - D’Andrea, Felipe B.
AU - Li, Shao Gang
AU - Ginell, Stephan L.
AU - Freundlich, Joel S.
AU - Alves, Cláudio Nahum
AU - Bailey, Scott
AU - Cohen, Keira A.
AU - Lamichhane, Gyanu
N1 - Funding Information:
This work was supported by National Institutes of Health awards DP2OD008459 and R21AI121805 and by Cystic Fibrosis Foundation award LAMICH16GO.
Funding Information:
Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. We thank CNPQ Brazilian Agency for financial support (process no. 407096/2016-7) and CHPC from South Africa and HiPerGator Computational Center at the University of Florida for computational resources.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Beta-lactams
KW - Carbapenem
KW - Cephalosporin
KW - L,D-transpeptidase
KW - Mycobacterium abscessus
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U2 - 10.1128/AAC.00866-17
DO - 10.1128/AAC.00866-17
M3 - Article
C2 - 28760902
AN - SCOPUS:85029755388
VL - 61
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 10
ER -