# Development of Drugs to Target Arginine Biosythesis in Mycobacterium tuberculosis

> **NIH NIH SC1** · UNIVERSITY OF TEXAS EL PASO · 2022 · $377,500

## Abstract

SUMMARY
Tuberculosis (TB) remains a significant global health problem causing 10 million new cases and 1.2 million
deaths just last year according to the World Health Organization (WHO). The single greatest impediment to TB
control is its ability to form persisters, the subpopulation of Mycobacterium tuberculosis (Mtb) cells that are
phenotypically resistant to killing by bactericidal drugs or immune effectors. We have discovered that arginine
starvation, induced by inoculating mutants of Mtb cells into arginine-free media or mice, mediates rapid
sterilization that kills both actively growing Mtb cells and Mtb persister cells both in vitro and in vivo. Moreover,
we have successfully determined the structure of the Mtb ArgB enzyme and used Fragment-Based Drug
Discovery (FBDD) to discover two scaffold compounds that bind and inhibit the enzymatic activity of ArgB. The
absence of the de novo arginine biosynthesis pathway enzymes Arg A, B, C, D, and J in humans and our
demonstration that Mtb cannot bypass argB or argF deletions make Arginine Biosynthetic Enzymes attractive
drug targets for TB drug development. Transcriptomic, metabolomics and flow-cytometric analyses on the
arginine starving cells have provided new insights into the sterilization process. By comparing arginine
starvation to three other sterilizing regimens, we identified a set of six genes that provide a sterilization
signature. We plan to exploit these genes for improved drug discovery, by identifying novel drugs to inhibit the
activity of Mtb ArgB using fragment-based drug design, confirm genetically any additional targets of the
arginine biosynthetic pathway to expand the drug target space, and determining the correlative or causative
role the common sterilizing signature genes play in Mtb sterilization. Together these studies will make available
a new way to rapidly sterilize cultures of Mtb and provide new drug possibilities and new insights to shorten TB
chemotherapy and treat drug-resistant TB.

## Key facts

- **NIH application ID:** 10396608
- **Project number:** 5SC1GM140968-02
- **Recipient organization:** UNIVERSITY OF TEXAS EL PASO
- **Principal Investigator:** Sangeeta Tiwari
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $377,500
- **Award type:** 5
- **Project period:** 2021-04-22 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396608

## Citation

> US National Institutes of Health, RePORTER application 10396608, Development of Drugs to Target Arginine Biosythesis in Mycobacterium tuberculosis (5SC1GM140968-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10396608. Licensed CC0.

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