"One-Two Punch": Synergistic ß-Lactam Combinations for Mycobacterium abscessus and Target Redundancy in the Inhibition of Peptidoglycan Synthesis Enzymes

David C Nguyen; Khalid M Dousa; Sebastian G Kurz; Sheldon T Brown; George Drusano; Steven M Holland; Barry N Kreiswirth; W Henry Boom; Charles L Daley; Robert A Bonomo

doi:10.1093/cid/ciab535

"One-Two Punch": Synergistic ß-Lactam Combinations for Mycobacterium abscessus and Target Redundancy in the Inhibition of Peptidoglycan Synthesis Enzymes

Clin Infect Dis. 2021 Oct 20;73(8):1532-1536. doi: 10.1093/cid/ciab535.

Authors

David C Nguyen^{1

2}, Khalid M Dousa³, Sebastian G Kurz⁴, Sheldon T Brown^{5

6}, George Drusano⁷, Steven M Holland⁸, Barry N Kreiswirth⁹, W Henry Boom^{1

10}, Charles L Daley¹¹, Robert A Bonomo^{12

13

14}

Affiliations

¹ Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
² Division of Pediatric Infectious Diseases, Rainbow Babies and Children's Hospital, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
³ Department of Internal Medicine and Infectious Diseases, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
⁴ Mount Sinai National Jewish Respiratory Institute, New York, New York, USA.
⁵ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Department of Medicine, James J. Peters VA Medical Center, Bronx, New York, USA.
⁷ Institute for Therapeutic Innovation, University of Florida, Orlando, Florida, USA.
⁸ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁹ Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.
¹⁰ Tuberculosis Research Unit, Case Western Reserve University, Cleveland, Ohio, USA.
¹¹ Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, Colorado, USA.
¹² Department of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics, and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
¹³ Medical Service, Research Service, and Geriatric Research Education and Clinical Centers (GRECC), Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
¹⁴ Case Western Reserve University (CWRU)-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, Ohio, USA.

Abstract

Mycobacterium abscessus subsp. abscessus is one of the most difficult pathogens to treat and its incidence in disease is increasing. Dual β-lactam combinations act synergistically in vitro but are not widely employed in practice. A recent study shows that a combination of imipenem and ceftaroline significantly lowers the minimum inhibitory concentration of clinical isolates, despite both drugs targeting the same peptidoglycan synthesis enzymes. The underlying mechanism of this effect provides a basis for further investigations of dual β-lactam combinations in the treatment of M. abscessus subsp. abscessus, eventually leading to a clinical trial. Furthermore, dual β-lactam strategies may be explored for other difficult mycobacterial infections.

Keywords: Mycobacterium abscessus; L,D-transpeptidase; ceftaroline; dual beta-lactam; imipenem.

MeSH terms

Anti-Bacterial Agents / pharmacology
Drug Synergism
Humans
Lactams
Microbial Sensitivity Tests
Mycobacterium Infections, Nontuberculous* / drug therapy
Mycobacterium abscessus*
Peptidoglycan

Substances

Anti-Bacterial Agents
Lactams
Peptidoglycan

Grants and funding

R01 AI141805/AI/NIAID NIH HHS/United States