Genetic Determinants of Intrinsic Antibiotic Tolerance in Mycobacterium avium.

William M Matern,Leah Hoover,Harley Parker,Petros C Karakousis,Joel S Bader,Carina Danchik,Kileen L Shier

doi:10.1128/spectrum.00246-21

Abstract

ABSTRACTThe Mycobacterium avium complex (MAC) is one of the most prevalent causes of nontuberculous mycobacteria pulmonary infection in the United States, and yet it remains understudied. Current MAC treatment requires more than a year of intermittent to daily combination antibiotic therapy, depending on disease severity. In order to shorten and simplify curative regimens, it is important to identify the innate bacterial factors contributing to reduced antibiotic susceptibility, namely, antibiotic tolerance genes. In this study, we performed a genome-wide transposon screen to elucidate M. avium genes that play a role in the bacterium’s tolerance to first- and second-line antibiotics. We identified a total of 193 unique M. avium mutants with significantly altered susceptibility to at least one of the four clinically used antibiotics we tested, including two mutants (in DFS55_00905 and DFS55_12730) with panhypersusceptibility. The products of the antibiotic tolerance genes we have identified may represent novel targets for future drug development studies aimed at shortening the duration of therapy for MAC infections.IMPORTANCE The prolonged treatment required to eradicate Mycobacterium avium complex (MAC) infection is likely due to the presence of subpopulations of antibiotic-tolerant bacteria with reduced susceptibility to currently available drugs. However, little is known about the genes and pathways responsible for antibiotic tolerance in MAC. In this study, we performed a forward genetic screen to identify M. avium antibiotic tolerance genes, whose products may represent attractive targets for the development of novel adjunctive drugs capable of shortening the curative treatment for MAC infections.

Highlights

The Mycobacterium avium complex (MAC) is one of the most prevalent causes of nontuberculous mycobacteria pulmonary infection in the United States, and yet it remains understudied
Antibiotic Tolerance Genes in M. avium obtained following antibiotic exposure for 0, 12, and 48 h are provided in Fig. S2 in the supplemental material
Given the strong effect sizes observed with MOX relative to the other antibiotics tested, MOX synthetic lethality may represent the greatest opportunity for novel treatment-shortening strategies

Summary

Introduction

The Mycobacterium avium complex (MAC) is one of the most prevalent causes of nontuberculous mycobacteria pulmonary infection in the United States, and yet it remains understudied. Current MAC treatment requires more than a year of intermittent to daily combination antibiotic therapy, depending on disease severity. The products of the antibiotic tolerance genes we have identified may represent novel targets for future drug development studies aimed at shortening the duration of therapy for MAC infections. IMPORTANCE The prolonged treatment required to eradicate Mycobacterium avium complex (MAC) infection is likely due to the presence of subpopulations of antibiotictolerant bacteria with reduced susceptibility to currently available drugs. We performed a forward genetic screen to identify M. avium antibiotic tolerance genes, whose products may represent attractive targets for the development of novel adjunctive drugs capable of shortening the curative treatment for MAC infections. If the infecting MAC strain is macrolideresistant or the patient is unable to take the first-line regimen, alternative antibiotics, such as moxifloxacin, clofazimine, or linezolid, are often used [11, 12]

Methods

Results

Conclusion