Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis
Authors
Bellerose, MichelleProulx, Megan K.
Smith, Clare M.
Baker, Richard E.
Ioerger, Thomas R.
Sassetti, Christopher M.
UMass Chan Affiliations
Department of Microbiology and Physiological SystemsDocument Type
Journal ArticlePublication Date
2020-08-04Keywords
Mycobacterium tuberculosisantibiotic treatment
host-microbe interactions
microbial genomics
Bacteria
Bacterial Infections and Mycoses
Bacteriology
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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.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
DOI
10.1128/mSystems.00396-20Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41546PubMed ID
32753506Related Resources
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Copyright © 2020 Bellerose et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1128/mSystems.00396-20
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Except where otherwise noted, this item's license is described as Copyright © 2020 Bellerose et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.