Antibiotic Bactericidal Activity Is Countered by Maintaining pH Homeostasis in Mycobacterium smegmatis

Author:

Bartek I. L.1,Reichlen M. J.1,Honaker R. W.1,Leistikow R. L.1,Clambey E. T.2,Scobey M. S.1,Hinds A. B.1,Born S. E.1,Covey C. R.1,Schurr M. J.1,Lenaerts A. J.3,Voskuil M. I.1

Affiliation:

1. Department of Immunology and Microbiology, University of Colorado—Denver, School of Medicine, Aurora, Colorado, USA

2. Department of Anesthesiology, University of Colorado—Denver, School of Medicine, Aurora, Colorado, USA

3. Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA

Abstract

Since the discovery of antibiotics, mortality due to bacterial infection has decreased dramatically. However, infections from difficult to treat bacteria such as Mycobacterium tuberculosis and multidrug-resistant pathogens have been on the rise. An understanding of the cascade of events that leads to cell death downstream of specific drug-target interactions is not well understood. We have discovered that killing by several classes of antibiotics was stopped by maintaining pH balance within the bacterial cell, consistent with a shared mechanism of antibiotic killing. Our findings suggest a mechanism of antibiotic killing that stems from the antibiotic’s ability to increase the pH within bacterial cells by disrupting proton entry without affecting proton pumping out of cells. Knowledge of the core mechanism necessary for antibiotic killing could have a significant impact on the development of new lethal antibiotics and for the treatment of recalcitrant and drug-resistant pathogens.

Funder

HHS | National Institutes of Health

Bill and Melinda Gates Foundation

Publisher

American Society for Microbiology

Subject

Molecular Biology,Microbiology

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