# Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes

> **NIH NIH U19** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $568,737

## Abstract

ABSTRACT - PROJECT 4
 Perhaps the greatest barrier to improving tuberculosis (TB) treatment outcomes is the six months of multi-
drug therapy that is required to reliably cure a patient with active disease. Lengthy therapy is both costly and
leads to poor adherence. This project aims to understand the bacterial factors responsible for lengthy TB
treatment, TB treatment failure, and relapse. Mycobacterium tuberculosis (Mtb), the causative agent of TB has
developed an exquisite ability to adapt to its environment. Drug treatment can lead to the development of
“phenotypically drug-resistant” (i.e. drug tolerant) subpopulations that persist for long periods, as well as atypical
very-low level drug resistant mutants (i.e. elevated sub-breakpoint MIC strains) that can eventually relapse
despite months of seemingly effective drug treatment. Our overriding hypothesis is that the length of time
required to treat TB and the adverse TB outcomes that can occur even with adequate therapy are strongly linked
to phenotypic drug resistance and low-level genetic drug resistance mechanisms that can be present in Mtb
subpopulation pre-treatment, or that arise during treatment. This project will apply novel tools we have
developed, including One-cell Doubling Evaluation of Living Arrays of Mycobacterium (ODELAM), a robotic
Transwell Tolerance and Resistance (TTR) system, a complete library of transcription factor inducible (TFI)
strains, and constitutively tolerant glpK mutant Mtb strains to investigate the mechanisms that underlie these
bacterial states, as well as the heterogeneous expression of tolerance and low level resistance in different Mtb
sub-populations. Expanding from well-defined laboratory strains to a diverse collection of well characterized
clinical Mtb strains associated with either cure or relapse, we will develop a mechanistic understanding of these
still poorly characterized bacterial phenotypes and their role in treatment outcome. These discoveries will lead
to important opportunities for developing targeted TB treatments that increase therapeutic success while
shortening treatment times. This work will be conducted in three related aims: Aim 1. Define the links between
heterogeneity and phenotypic drug tolerance in Mtb. Aim 2. Determine the role of Mtb phase variation on
population heterogeneity, drug tolerance and emergent drug resistance. Aim 3. Assess role(s) of genes,
networks, and population heterogeneity in clinical isolates with defined treatment-related phenotypes.

## Key facts

- **NIH application ID:** 10271651
- **Project number:** 1U19AI162598-01
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** DAVID R SHERMAN
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $568,737
- **Award type:** 1
- **Project period:** 2021-09-23 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271651

## Citation

> US National Institutes of Health, RePORTER application 10271651, Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes (1U19AI162598-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10271651. Licensed CC0.

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