# Minimizing in vivo Drug Tolerance induction in tuberculosis.

> **NIH NIH U19** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $608,113

## Abstract

Abstract Project 3: Minimizing in vivo drug tolerance induction in tuberculosis.
Phenotypic drug tolerance in Mycobacterium tuberculosis is an expression of one of the single most significant
properties that make Mtb such a major Global Health threat. Tolerance promotes bacterial persistence in the
face of drug therapy and expands the window for emergence of genetically-encoded resistance. The goal of the
project is the rational design of a novel therapeutic approach to minimize the induction of drug tolerance through
manipulation of the host cells or the immune environment that result in drug tolerance. Such an outcome would
enhance the efficacy of current TB drug regimens and reduce emergence of heritable drug resistance.
 To accomplish this goal, we will leverage a number of recent advances from our labs. The Russell lab has
developed the capability to simultaneously profile host and pathogen transcriptomes in cells isolated directly
from drug-treated animals. The Sassetti lab has developed a complementary genetic database that
comprehensively quantifies the effect of bacterial mutations on drug tolerance during infection, and has exploited
CRISPR-Cas9 to engineer the genomes of primary macrophage lines.
 The overarching hypothesis guiding this project is that phenotypic drug tolerance in Mtb is induced by
the host immune environment, which can be specifically modulated to increase drug efficacy.
Aim 1: Identify macrophage immune or metabolic pathways that influence Mtb drug tolerance.
We will apply different RNA-seq modalities to infected macrophages from the lungs of antibiotic-treated mice to
identify host pathways that are linked with the expression of tolerance-related bacterial genes. Integrating diverse
Mtb isolates will link these mechanistic observations to clinically-relevant phenotypes.
Aim 2: Characterize mechanistic links between macrophage metabolic state and Mtb drug tolerance.
We will exploit emergent genetic tools to probe bacterial and host macrophage biology for the functional
verification of candidate pathways leading to induction of drug tolerance in Mtb. We will use a combination of
culture and host cell model systems to link specific immune pathways to induction of bacterial drug tolerance.
Aim 3: Proof-of-Concept for therapeutic interventions to maintain/enhance frontline drug efficacy.
We will use synthetic mRNA and siRNA approaches to explore avenues whereby in vivo drug tolerance can be
minimized and the efficacy of frontline drugs can be effectively sustained. A combination of reductionist animal
models and human clinical specimens will be used to link mechanism with therapeutic relevance.

## Key facts

- **NIH application ID:** 10271650
- **Project number:** 1U19AI162598-01
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** DAVID G RUSSELL
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $608,113
- **Award type:** 1
- **Project period:** 2021-09-23 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271650

## Citation

> US National Institutes of Health, RePORTER application 10271650, Minimizing in vivo Drug Tolerance induction in tuberculosis. (1U19AI162598-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10271650. Licensed CC0.

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