# Metabolite modulation of Mtb regulators of cell wall biogenesis

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $481,646

## Abstract

PROJECT SUMMARY
 Despite the availability of antibiotics to combat Tuberculosis (TB), it is one of the leading causes of death
due to infectious disease. Mycobacterium tuberculosis (Mtb) is a successful pathogen because it survives
within immune cells and effectively establishes and maintains a latent TB infection. Therefore, understanding
the mechanisms underlying the establishment or maintenance of dormancy can inform new strategies for TB
therapeutics.
 Mycobacterial membrane protein large (MmpL) proteins are dedicated cell wall lipid transporters. Along
with their accessory Mycobacterial membrane protein small (MmpS) proteins, these transporters are crucial
players in mycobacterial physiology and pathogenesis. MmpL3 is essential; and MmpL4, MmpL5, MmpL7,
MmpL8, MmpL10 and MmpL11 contribute to Mtb virulence. The related proteins MmpL3 and MmpL11 that
transport mycolic acid-containing lipids are of particular interest to us. MmpL3 transports trehalose
monomycolate and is required for mycobacterial replication and viability. We showed that MmpL11 transports
monomeromycolyl diacylglycerol and a mycolate ester wax. These are species of lipids that are sometimes
referred to as “storage lipids” and are associated with dormant bacteria in vitro and accumulate in granulomas
of TB patients. Therefore, it appears that MmpL11 plays a role in a clinically relevant, but poorly understood,
aspect of Mtb pathogenesis.
 While significant advances have been made identifying MmpL substrates, the regulation of MmpL protein
expression and their role in cell wall remodeling in different environmental conditions has not been explored.
The proposed studies will characterize the structure and function of Mtb transcriptional regulators that control
expression of essential and virulence-associated MmpL and MmpS proteins. Our preliminary data indicate that
fatty acids directly modulate activity of these unique transcription factors. This suggests a model where Mtb
can directly assess and respond to fatty acid intermediates, metabolic state and nutrient availability to control
mmpL and mmpS gene regulation. By defining the molecular mechanisms underlying the regulation of MmpL
transporters and identifying their regulons, we will generate novel insights into the transition between actively
dividing Mtb and latent or non-replicating persistent Mtb.
!

## Key facts

- **NIH application ID:** 10053297
- **Project number:** 5R01AI123148-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Georgiana E. Purdy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $481,646
- **Award type:** 5
- **Project period:** 2016-11-25 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053297

## Citation

> US National Institutes of Health, RePORTER application 10053297, Metabolite modulation of Mtb regulators of cell wall biogenesis (5R01AI123148-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10053297. Licensed CC0.

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