UMMS Affiliation

Department of Microbiology and Physiological Systems

Publication Date

2020-08-04

Document Type

Article

Disciplines

Bacteria | Bacterial Infections and Mycoses | Bacteriology

Abstract

Effective tuberculosis treatment requires at least 6 months of combination therapy. Alterations in the physiological state of the bacterium during infection are thought to reduce drug efficacy and prolong the necessary treatment period, but the nature of these adaptations remain incompletely defined. To identify specific bacterial functions that limit drug effects during infection, we employed a comprehensive genetic screening approach to identify mutants with altered susceptibility to the first-line antibiotics in the mouse model. We identified many mutations that increase the rate of bacterial clearance, suggesting new strategies for accelerating therapy. In addition, the drug-specific effects of these mutations suggested that different antibiotics are limited by distinct factors. Rifampin efficacy is inferred to be limited by cellular permeability, whereas isoniazid is preferentially affected by replication rate. Many mutations that altered bacterial clearance in the mouse model did not have an obvious effect on drug susceptibility using in vitro assays, indicating that these chemical-genetic interactions tend to be specific to the in vivo environment. This observation suggested that a wide variety of natural genetic variants could influence drug efficacy in vivo without altering behavior in standard drug-susceptibility tests. Indeed, mutations in a number of the genes identified in our study are enriched in drug-resistant clinical isolates, identifying genetic variants that may influence treatment outcome. Together, these observations suggest new avenues for improving therapy, as well as the mechanisms of genetic adaptations that limit it.

IMPORTANCE Understanding how Mycobacterium tuberculosis survives during antibiotic treatment is necessary to rationally devise more effective tuberculosis (TB) chemotherapy regimens. Using genome-wide mutant fitness profiling and the mouse model of TB, we identified genes that alter antibiotic efficacy specifically in the infection environment and associated several of these genes with natural genetic variants found in drug-resistant clinical isolates. These data suggest strategies for synergistic therapies that accelerate bacterial clearance, and they identify mechanisms of adaptation to drug exposure that could influence treatment outcome.

Keywords

Mycobacterium tuberculosis, antibiotic treatment, host-microbe interactions, microbial genomics

Rights and Permissions

Copyright © 2020 Bellerose et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

DOI of Published Version

10.1128/mSystems.00396-20

Source

Bellerose MM, Proulx MK, Smith CM, Baker RE, Ioerger TR, Sassetti CM. Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis. mSystems. 2020 Aug 4;5(4):e00396-20. doi: 10.1128/mSystems.00396-20. PMID: 32753506; PMCID: PMC7406225. Link to article on publisher's site

Journal/Book/Conference Title

mSystems

Related Resources

Link to Article in PubMed

PubMed ID

32753506

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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