# Establishing the Genetic Basis of Altered Drug Responses in Mycobacterium tuberculosis

> **NIH NIH U19** · HARVARD MEDICAL SCHOOL · 2022 · $990,348

## Abstract

Summary
High-level drug resistance puts TB patients at increased risk of treatment failure.
However, patients also fail treatment with apparently drug susceptible strains even in
clinical trial settings where compliance is well monitored. We postulate that decades of
drug exposure have selected for bacterial strains that have alterations in drug-mediated
clearance that are not identified by conventional drug resistance testing and that these
changes put compromise patient outcomes. In previous work, we identified mutations
that alter bacterial drug susceptibility in ways that are not identified by conventional
clinical resistance testing but are revealed by assaying bacterial drug responses using
time-dependent killing assays under host-like environmental conditions. We hypothesize
that these mutations predispose to treatment failure even as they also accelerate the
emergence of high-level drug resistance. To test this hypothesis, we propose to test the
hypothesis that mutations associated with resistance and treatment failure in clinical
cohorts alter Mtb survival in the presence of antibiotics. For this aim, we will construct
and phenotype a barcoded library of isogenic strains carrying mutations identified in our
analyses of clinical strains as associated with drug resistance or treatment failure. We
will test the hypothesis that the drug resistance-associated mutations and mutations
associated with treatment failure cause treatment failure in a mouse model of infection.
Finally, because many resistance associated mutations appear to cause multidrug
tolerance, we will assess their effects on the efficacy of new antibiotics and small
molecules in late stage development for Mtb.

## Key facts

- **NIH application ID:** 10390301
- **Project number:** 5U19AI142793-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** SARAH FORTUNE
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $990,348
- **Award type:** 5
- **Project period:** 2019-04-18 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390301

## Citation

> US National Institutes of Health, RePORTER application 10390301, Establishing the Genetic Basis of Altered Drug Responses in Mycobacterium tuberculosis (5U19AI142793-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10390301. Licensed CC0.

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