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Experimental Therapeutics

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
Pankaj Kumar
aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
bTaskforce To Study Resistance Emergence and Antimicrobial Development Technology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Varsha Chauhan
aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
bTaskforce To Study Resistance Emergence and Antimicrobial Development Technology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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José Rogério A. Silva
cPrograma de Pós-Graduação em Química Medicinal e Modelagem Molecular, Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém, Pará, Brazil
dLaboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, Pará, Brazil
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Jerônimo Lameira
cPrograma de Pós-Graduação em Química Medicinal e Modelagem Molecular, Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém, Pará, Brazil
dLaboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, Pará, Brazil
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Felipe B. d'Andrea
bTaskforce To Study Resistance Emergence and Antimicrobial Development Technology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Shao-Gang Li
eDepartments of Pharmacology, Physiology and Neuroscience, and Medicine, Rutgers University, Newark, New Jersey, USA
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Stephan L. Ginell
fBiosciences Division, Argonne National Laboratory, Argonne, Illinois, USA
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Joel S. Freundlich
eDepartments of Pharmacology, Physiology and Neuroscience, and Medicine, Rutgers University, Newark, New Jersey, USA
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Cláudio Nahum Alves
cPrograma de Pós-Graduação em Química Medicinal e Modelagem Molecular, Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém, Pará, Brazil
dLaboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, Pará, Brazil
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Scott Bailey
gDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
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Keira A. Cohen
hDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
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Gyanu Lamichhane
aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
bTaskforce To Study Resistance Emergence and Antimicrobial Development Technology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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  • ORCID record for Gyanu Lamichhane
DOI: 10.1128/AAC.00866-17
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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 β-lactams determines their activity against Mycobacterium tuberculosis. Here, we studied the interactions of β-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 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 pansusceptible M. abscessus and clinical isolates that are resistant to most antibiotics, which suggests that dual-β-lactam therapy has potential for the treatment of M. abscessus. Finally, we solved the first crystal structure of an M. abscessusl,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 against M. abscessus.

FOOTNOTES

    • Received 24 April 2017.
    • Returned for modification 12 May 2017.
    • Accepted 21 July 2017.
    • Accepted manuscript posted online 31 July 2017.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00866-17 .

  • Copyright © 2017 American Society for Microbiology.

All Rights Reserved .

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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
Antimicrobial Agents and Chemotherapy Sep 2017, 61 (10) e00866-17; DOI: 10.1128/AAC.00866-17

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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
Antimicrobial Agents and Chemotherapy Sep 2017, 61 (10) e00866-17; DOI: 10.1128/AAC.00866-17
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KEYWORDS

Anti-Bacterial Agents
carbapenems
cephalosporins
Mycobacterium abscessus
penicillins
peptidoglycan
Peptidyl Transferases
l,d-transpeptidase
Mycobacterium abscessus
beta-lactams
carbapenem
cephalosporin

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