# Antibiotic tolerance as a stepping stone to tuberculosis drug-resistance

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $212,350

## Abstract

PROJECT SUMMARY
Antibiotic tolerance describes differential susceptibility of an isogenic bacterial population to bactericidal
antibiotics. Antibiotic tolerance contributes to two clinically relevant phenotypes: populations with increased
antibiotic tolerance are harder to eradicate and need prolonged antibiotic therapy – a hallmark of tuberculosis;
and antibiotic tolerance has been shown in some organisms to act as a stepping stone to bona fide drug-
resistance. However, there are many forms of antibiotic tolerance – ranging from non-replicating persisters to
growing phenotypic resister cells – and these most likely represent diverse physiological states, mediated by
distinct molecular mechanisms. The relative prevalence of these forms of tolerance in clinical isolates of
Mycobacterium tuberculosis – the cause of tuberculosis – is completely unknown, as is the relative contribution
of distinct types of tolerance to in vivo antibiotic susceptibility and development of antibiotic resistance. We have
developed assays that can measure the relative tolerant subpopulation caused by non-replicating persistence
and growing phenotypic resistance to the first-line anti-TB antibiotic rifampicin. Using these assays, we will
measure the relative prevalence of these distinct forms of tolerance in clinical isolates of M. tuberculosis
representing all major phylogenetic groups. By transposon insertion mutagenesis and deep-sequencing (Tnseq),
we will dissect the genetic requirements for tolerance both in vitro and in a novel murine model of tuberculosis
infection, using B6.Sp140 -/- mice that recapitulate the hallmarks of infection such as necrotic granulomata of
C3H/FeJ ‘Kramnik’ mice. We will also determine the contribution of these two forms of rifampicin tolerance to
the development of rifampicin-resistance in select clinical isolates of M. tuberculosis, and perform Tnseq to
identify genetic contributors to resistance. Together, these studies will further our understanding of the molecular
mechanisms of distinct forms of rifampicin tolerance in clinical strains of tuberculosis, and their relevance to the
development of genetic resistance.

## Key facts

- **NIH application ID:** 10592979
- **Project number:** 1R21AI169005-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Babak Javid
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $212,350
- **Award type:** 1
- **Project period:** 2023-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592979

## Citation

> US National Institutes of Health, RePORTER application 10592979, Antibiotic tolerance as a stepping stone to tuberculosis drug-resistance (1R21AI169005-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10592979. Licensed CC0.

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