Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

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 incompletel...

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Autores principales:	Michelle M. Bellerose, Megan K. Proulx, Clare M. Smith, Richard E. Baker, Thomas R. Ioerger, Christopher M. Sassetti
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	antibiotic treatment host-microbe interactions microbial genomics Mycobacterium tuberculosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/23c0875585844471b522ef08ddde1029
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spelling	oai:doaj.org-article:23c0875585844471b522ef08ddde10292021-12-02T18:15:46ZDistinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mSystems.00396-202379-5077https://doaj.org/article/23c0875585844471b522ef08ddde10292020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00396-20https://doaj.org/toc/2379-5077ABSTRACT 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.Michelle M. BelleroseMegan K. ProulxClare M. SmithRichard E. BakerThomas R. IoergerChristopher M. SassettiAmerican Society for Microbiologyarticleantibiotic treatmenthost-microbe interactionsmicrobial genomicsMycobacterium tuberculosisMicrobiologyQR1-502ENmSystems, Vol 5, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	antibiotic treatment host-microbe interactions microbial genomics Mycobacterium tuberculosis Microbiology QR1-502
spellingShingle	antibiotic treatment host-microbe interactions microbial genomics Mycobacterium tuberculosis Microbiology QR1-502 Michelle M. Bellerose Megan K. Proulx Clare M. Smith Richard E. Baker Thomas R. Ioerger Christopher M. Sassetti Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
description	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.
format	article
author	Michelle M. Bellerose Megan K. Proulx Clare M. Smith Richard E. Baker Thomas R. Ioerger Christopher M. Sassetti
author_facet	Michelle M. Bellerose Megan K. Proulx Clare M. Smith Richard E. Baker Thomas R. Ioerger Christopher M. Sassetti
author_sort	Michelle M. Bellerose
title	Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_short	Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full	Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_fullStr	Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full_unstemmed	Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_sort	distinct bacterial pathways influence the efficacy of antibiotics against <named-content content-type="genus-species">mycobacterium tuberculosis</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/23c0875585844471b522ef08ddde1029
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Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

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