# Project 2: Response to Treatment

> **NIH NIH U19** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $584,650

## Abstract

Abstract – Project 2
The responses of Mtb to individual drugs and regimens and their relationship to treatment outcome remains
variable and poorly understood. Our premise is that knowledge of bacterial networks and their regulatory
controls constitute a powerful but underexplored window to novel targets and treatment strategies.
The major goal of this project is to identify strain-independent and strain-specific cellular networks associated
with varying drug responses in Mtb, and their regulation. In Aim 1 this project will utilize carefully selected
clinical drug-sensitive Mtb isolates exhibiting varying responses to treatment to characterize the genetic,
transcriptional, and metabolic differences revealed by exposure to important anti-TB drugs, and then to map
those changes to condition-specific drug tolerance phenotypes. We will subject each strain to detailed
analyses including transcriptomics, metabolomics, and regulator-based genetic screens in response to front
line antibiotics and in conditions that promote tolerance. In Aim 2 we will employ the data from Aim 1 to
build and refine regulatory network models that elucidate both common and strain-specific Mtb strategies to
subvert drug action. These models will be refined by testing model driven predictions through an iterative
series of multi-omic analyses and perturbations including more focused experiments such as targeted
protein interaction studies, bacterial cell sorting and solid-phase time-lapse microscopy. Ultimately, in Aim 3
we will test the extent to which the drug-response network models generated in Aims 1 and 2 predict clinical
treatment outcomes, and identify potential strategies to interfere with adaptive drug-response network states
to improve the efficacy of chemotherapy. We will further test the relevance of identified drug response
networks in targeted studies of Mtb isolates from treatment failures in humans. The outcome of this project
will be the identification and validation of the specific cellular networks associated with varying drug
responses in Mtb and their regulation.

## Key facts

- **NIH application ID:** 10102185
- **Project number:** 5U19AI135976-05
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** DAVID R SHERMAN
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $584,650
- **Award type:** 5
- **Project period:** 2018-02-12 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102185

## Citation

> US National Institutes of Health, RePORTER application 10102185, Project 2: Response to Treatment (5U19AI135976-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10102185. Licensed CC0.

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