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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2020-08-01
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| Series: | mSystems |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSystems.00396-20 |
| _version_ | 1818691872844939264 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-17T12:48:48Z |
| format | Article |
| id | doaj.art-23c0875585844471b522ef08ddde1029 |
| institution | Directory Open Access Journal |
| issn | 2379-5077 |
| language | English |
| last_indexed | 2024-12-17T12:48:48Z |
| publishDate | 2020-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSystems |
| spelling | doaj.art-23c0875585844471b522ef08ddde10292022-12-21T21:47:40ZengAmerican Society for MicrobiologymSystems2379-50772020-08-015410.1128/mSystems.00396-20Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>Michelle M. Bellerose0Megan K. Proulx1Clare M. Smith2Richard E. Baker3Thomas R. Ioerger4Christopher M. Sassetti5Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USADepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USADepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USADepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USADepartment of Computer Science and Engineering, Texas A&M University, College Station, Texas, USADepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mSystems.00396-20antibiotic treatmenthost-microbe interactionsmicrobial genomicsMycobacterium tuberculosis |
| spellingShingle | 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> mSystems antibiotic treatment host-microbe interactions microbial genomics Mycobacterium tuberculosis |
| title | 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_short | 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 |
| topic | antibiotic treatment host-microbe interactions microbial genomics Mycobacterium tuberculosis |
| url | https://journals.asm.org/doi/10.1128/mSystems.00396-20 |
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