A Mycobacterium Tuberculosis NBTI DNA Gyrase Inhibitor Is Active Against Mycobacterium Abscessus

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2021 Oct 4

PMID 34606340

Citations 11

Authors

Uday S Ganapathy

Ruben Gonzalez Del Rio

Monica Cacho-Izquierdo

Fatima Ortega

Joel Lelievre

David Barros-Aguirre

Wassihun Wedajo Aragaw

Matthew D Zimmerman

Marissa Lindman

Veronique Dartois

Martin Gengenbacher

Thomas Dick

Affiliations

Soon will be listed here.

Abstract

Fluoroquinolones-the only clinically used DNA gyrase inhibitors-are effective against tuberculosis (TB) but are in limited clinical use for nontuberculous mycobacteria (NTM) lung infections due to intrinsic drug resistance. We sought to test alternative DNA gyrase inhibitors for anti-NTM activity. Mycobacterium tuberculosis gyrase inhibitors (MGIs), a subclass of novel bacterial topoisomerase inhibitors (NBTIs), were recently shown to be active against the tubercle bacillus. Here, we show that the MGI EC/11716 not only has potent anti-tubercular activity but is active against M. abscessus and M. avium . Focusing on M. abscessus, which causes the most difficult to cure NTM disease, we show that EC/11716 is bactericidal, active against drug-tolerant biofilms, and efficacious in a murine model of M. abscessus lung infection. Based on resistant mutant selection experiments, we report a low frequency of resistance to EC/11716 and confirm DNA gyrase as its target. Our findings demonstrate the potential of NBTIs as anti-M. abscessus and possibly broad-spectrum anti-mycobacterial agents.

Citing Articles

Anti-Mycobacterial Activity of Bacterial Topoisomerase Inhibitors with Dioxygenated Linkers.

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Molecular mechanism of a triazole-containing inhibitor of DNA gyrase.

Gedeon A, Yab E, Dinut A, Sadowski E, Capton E, Dreneau A iScience. 2024; 27(10):110967.

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Dartois V, Dick T Clin Microbiol Rev. 2024; 37(4):e0008023.

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Role of DNA Double-Strand Break Formation in Gyrase Inhibitor-Mediated Killing of Nonreplicating Persistent in Caseum.

Ashwath P, Osiecki P, Weiner D, Via L, Sarathy J ACS Infect Dis. 2024; 10(10):3631-3639.

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Preclinical murine models for the testing of antimicrobials against Mycobacterium abscessus pulmonary infections: Current practices and recommendations.

Dartois V, Bonfield T, Boyce J, Daley C, Dick T, Gonzalez-Juarrero M Tuberculosis (Edinb). 2024; 147:102503.

PMID: 38729070 PMC: 11168888. DOI: 10.1016/j.tube.2024.102503.

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