# Metabolic determinants of barrier function in rifampin-sensitive and -resistant Mtb

> **NIH NIH U19** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $454,485

## Abstract

Project 2 - Metabolic determinants of barrier function in rifampin-sensitive and -resistant Mtb
Project Leader: Kyu Rhee
Co-investigator: Valerie Mizrahi
Collaborating investigators: Jeremy Rock (Core D), D. Branch Moody (Core B)
ABSTRACT
The overarching goal of this project is to elucidate specific cell envelope structure-activity relationships
mediating barrier function. A key and quite literal barrier to safer and simpler drugs and treatments for TB is its
highly unusual cell envelope. Improved knowledge of the barrier function of the Mtb envelope thus represents a
potential blueprint to developing better safer drugs. Unlike most bacteria, the Mycobacterium tuberculosis (Mtb)
envelope consists in a unique multilayered structure whose physico-chemical properties are widely believed to
mediate an intrinsic mechanism of antibiotic resistance. Using newly developed whole organism chemical
profiling and genome scale CRISPRi technologies, we challenge the longstanding view of Mtb cell wall as a
static and impermeant chemical barrier. Preliminary studies indicate that the Mtb cell envelope is chemically
selective, and its barrier activity is not a simple product of its bulk physico-chemical properties. These data
further show that both its composition and barrier function are dynamically regulated. This project specifically
focuses on Mtb barrier function through the therapeutic lens of the frontline TB drug rifampicin. We focus on
rifampicin because of its unique treatment shortening and sterilizing activities against drug-sensitive TB, and its
defining role in the biology of drug-resistant TB. In addition, because rifampicin has a single, well understood
target of action, the b subunit of RNA polymerase, which is located in the cytosol, it serves as a potential model
that could elucidate general principles that apply to any drug with cytosolic targets.

## Key facts

- **NIH application ID:** 10271485
- **Project number:** 1U19AI162584-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Kyu Y Rhee
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $454,485
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271485

## Citation

> US National Institutes of Health, RePORTER application 10271485, Metabolic determinants of barrier function in rifampin-sensitive and -resistant Mtb (1U19AI162584-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10271485. Licensed CC0.

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