# Metabolic determinants of Mtb virulence, vulnerability and variation

> **NIH NIH U19** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $2,610,899

## Abstract

ABSTRACT - Metabolic determinants of Mtb virulence, vulnerability and variation
Mycobacterium tuberculosis (Mtb) has emerged as the world's most deadly pathogen based in large part on
the highly unusual biological and chemical properties of its cell envelope. Comprised of a distinctive
hydrophobic outer mycolate membrane, anchored to an underlying complex of polysaccharide and
peptidoglycan polymers, the Mtb envelope serves as both the primary interface with, and barrier to, the human
host. In human tuberculosis (TB) disease the Mtb envelope mediates a years-long standoff, and serves as the
barrier to all anti-mycobacterial drugs. Yet, knowledge of its native composition, variation and regulation of
drug entry remains fragmentary. This team of applicants has created new genetic and metabolomic tools to
comprehensively dissect and analyze the metabolite and lipid components of the Mtb envelope on an
organism-wide basis across a large set of clinical isolates. Moreover, this TBRU proposes to provide the first
descriptions of cell envelope variation among isolates from human patients and identify key determinants of its
virulence and barrier to drug action that could inform the development of better diagnostics and therapeutics.
Structures of new molecules will first be determined using synthetic chemistry and mass spectrometry. The
genes encoding these metabolites will then be identified and functionally validated using new genome-scale
CRISPR interference technologies, assays for penetration into the cell envelope, and genetically defined
mouse models of in vivo growth. Using mass spectrometry, we will solve the structures of up to 250 surface
barrier lipids and more than 41 gene-lipid pairs that dominate in cell envelope variation among patients.
Patient-derived Mtb strains will be obtained from clinical samples collected at our field sites in Masiphumelele,
South Africa, where we will implement clinically relevant technology for detection of live Mtb in exhaled (non-
coughed) human bioaerosols. Studies of barrier function place special emphasis on rifampicin as a model
compound due to its clinical importance as a frontline drug and role as a defining element of drug resistant TB.
The ability to analyze patient urine and serum has further resulted in the discovery of new biomarkers of
disease activity and response to drug therapy, motivating linked translational efforts to advance the
development of non-sputum based, real time point-of-care diagnostic tests. This highly interactive group of
scientists thus seeks to provide better drugs and diagnostic tests, as well as a deep and durable scientific
foundation for understanding of the Mtb envelope, especially the particular genes and molecules that control
active remodeling, drug action and human host response.

## Key facts

- **NIH application ID:** 10834925
- **Project number:** 5U19AI162584-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** DAVID Branch MOODY
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,610,899
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834925

## Citation

> US National Institutes of Health, RePORTER application 10834925, Metabolic determinants of Mtb virulence, vulnerability and variation (5U19AI162584-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10834925. Licensed CC0.

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