# Metabolic compensation in Mycobacterium tuberculosis for the formation of persisters

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $206,250

## Abstract

Research Summary
Metabolic networks in biological systems are functionally interconnected and mutually complementary, such that
malfunctions in one network are compensated for by other networks, a process termed adaptive metabolism.
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB) and utilizes this strategy to form
persisters, a phenotypic variant that survives under external stresses such as antibiotics, thus contributing to
species conservation. The ability of Mtb to undergo adaptive metabolism, thus ensuring persistence in the host
and maximizing tolerance against host environmental stresses, is responsible for the prolonged nature of
standard TB chemotherapies. Therefore, new therapeutic options that prevent adaptive metabolism and
subsequent persister formation are urgently needed, but scientific knowledge regarding persister formation in
Mtb is scant due to lack of in vitro persister reconstitution systems and optimal analytical techniques.
Here, we seek to overcome these hurdles by incorporating an in vitro biofilm system, FACS, and cutting-edge
metabolomics. Our new methodologies will enable us to pinpoint the adaptive metabolic mechanism specific to
Mtb persisters. We’ve shown that Mtb persisters downregulate electron transport chain (ETC) activity to reduce
the production of deleterious reactive radicals, meanwhile, activate adaptive metabolism to correct malfunctional
networks due to the absence of canonical ETC activity. Using our in vitro biofilm/FACS method, we selectively
isolated Mtb persisters and revealed that altered trehalose metabolism compensated for a decrease in ETC
activity, but Mtb deficient in trehalose metabolism are still able to form persisters at a density similar to that of
wild type, albeit after a significant initial delay. Collectively, these data indicate that Mtb is equipped with
multilayered adaptive strategies for persister formation. We will use our new method to selectively isolate
persisters derived from wild type Mtb or trehalose metabolism deficient Mtb to delineate trehalose metabolism I.
mediated and II. independent adaptive activities. Once the functional essentiality of I and II for persister formation
are validated, we will exploit the relative contribution of I and/or II for metabolic adaptive activities to drug-
tolerance. This project will significantly advance our insight into the ability of Mtb to adapt to antibiotic stresses
and hostile host environments. We anticipate the identification and exploration of new drug targets to improve
our control over the TB pandemic.

## Key facts

- **NIH application ID:** 9880433
- **Project number:** 5R21AI139386-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Hyungjin Eoh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $206,250
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880433

## Citation

> US National Institutes of Health, RePORTER application 9880433, Metabolic compensation in Mycobacterium tuberculosis for the formation of persisters (5R21AI139386-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9880433. Licensed CC0.

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