Transcriptional Inhibition of the F1F0-Type ATP Synthase Has Bactericidal Consequences on the Viability of Mycobacteria

Matthew B McNeil; Heath W K Ryburn; Liam K Harold; Justin F Tirados; Gregory M Cook

doi:10.1128/AAC.00492-20

Transcriptional Inhibition of the F₁F₀-Type ATP Synthase Has Bactericidal Consequences on the Viability of Mycobacteria

Antimicrob Agents Chemother. 2020 Jul 22;64(8):e00492-20. doi: 10.1128/AAC.00492-20. Print 2020 Jul 22.

Authors

Matthew B McNeil^{1

2}, Heath W K Ryburn³, Liam K Harold^{3

2}, Justin F Tirados³, Gregory M Cook^{3

2}

Affiliations

¹ Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand matthew.mcneil@otago.ac.nz.
² Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
³ Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.

Abstract

Bedaquiline, an inhibitor of the mycobacterial ATP synthase, has revolutionized the treatment of Mycobacterium tuberculosis infection. Although a potent inhibitor, it is characterized by poorly understood delayed time-dependent bactericidal activity. Here, we demonstrate that in contrast to bedaquiline, the transcriptional inhibition of the ATP synthase in M. tuberculosis and Mycobacterium smegmatis has rapid bactericidal activity. These results validate the mycobacterial ATP synthase as a drug target with the potential for rapid bactericidal activity.

Keywords: ATP synthase; CRISPRi; tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate
Antitubercular Agents / pharmacology
Humans
Mycobacterium smegmatis / genetics
Mycobacterium tuberculosis* / genetics
Tuberculosis*

Substances

Antitubercular Agents
Adenosine Triphosphate