# Interplay between the Mtb electron transport chain and carbon metabolism

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $399,102

## Abstract

Tuberculosis, caused by the etiological agent Mycobacterium tuberculosis (Mtb), is the leading cause of death
worldwide from a curable infectious agent and is becoming a major concern due to the spread of drug resistant
Mtb strains. Notably, Mtb can persist in a dormant, drug resistant state, sometimes reactivating to cause TB
decades after the primary infection. Currently, there is strong interest in exploiting oxidative phosphorylation
(OXPHOS) as a metabolic target for new anti-TB drugs and drug combinations. In this regard, there are several
antimycobacterial drugs that target the Mtb electron transport chain (ETC), including bedaquiline (the first new
TB drug in ~40 years), Q203, clofazimine, and phenothiazines. However, how inhibition of respiratory complexes
in the ETC leads to effective killing has yet to be established. We believe there is a critical gap in our
understanding of how OXPHOS communicates with central carbon catabolism in response to changing
environmental fuel sources to survive the host immune response and anti-TB drug therapy.
 Our long-term goal is to define the bioenergetic mechanisms that enable Mtb to survive within the host
in a dormant, drug resistant state. In this proposal, our central hypothesis is that the interplay between the Mtb
ETC and central carbon catabolism prevents effective killing by anti-TB drugs. To test this hypothesis, we have
established a series of specific aims to determine how OXPHOS-generated ATP modulates central carbon
catabolism and succinate excretion to maintain metabolic homeostasis, examine the mechanisms whereby
simultaneous inhibition of OXPHOS and glycolysis kills Mtb, and test the hypothesis that bioenergetic
homeostasis in clinical strains of Mtb contributes to drug tolerance. We will make use of a novel technology
termed extracellular flux (XF) analysis that we have adapted for studying Mtb bioenergetics in real time. This
technology will be complemented by 13C stable isotope analyses using liquid chromatography mass spectrometry
 This contribution is significant, because it has the potential to identify a new paradigm that will lead to a
detailed mechanistic understanding of how the Mtb ETC communicates with central carbon catabolism, and how
disruption of this process could be exploited to sterilize Mtb. This proposal is innovative in our opinion, because
the newly adapted technology that is supported by metabolomics, distinguish itself from conventional approaches
for studying energy metabolism in pathogenic microbes.

## Key facts

- **NIH application ID:** 10053296
- **Project number:** 5R01AI137043-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** ADRIE JC STEYN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,102
- **Award type:** 5
- **Project period:** 2018-11-07 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053296

## Citation

> US National Institutes of Health, RePORTER application 10053296, Interplay between the Mtb electron transport chain and carbon metabolism (5R01AI137043-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10053296. Licensed CC0.

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