# Turning Mycobacterium tuberculosis appetite for fatty acids against itself

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $254,250

## Abstract

Project summary
Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. In 2020, it is estimated that 1.5
million people died from TB. This calls for improved treatment regimens, which will greatly benefit from the
identification of novel strategies to sterilize infections. The overarching idea of this line of research is to subvert
highly adaptive strategies employed by the etiological agent of TB Mycobacterium tuberculosis (Mtb). There is a
large body of work in support of Mtb exploiting host fatty acids as a carbon source. However, although important
for growth and survival, fatty acids can also be toxic for Mtb. Previous work from our laboratory showed that
mutants devoid of malate synthase (glcB), type-2 NADH dehydrogenase (ndh/ ndhA) and EtfD (etfD) render a
fatty acid sensitive phenotype associated with attenuation in the mouse model of TB. This showed that it is
possible to turn Mtb’s optimized metabolism to oxidize host fatty acids against the bacilli. Beyond these specific
cases, there is a gap in knowledge on the genetic determinants necessary for Mtb to avoid fatty acid toxicity. To
address this issue, we have performed transposon sequencing (Tn-seq) and compared transposon mutant
libraries generated in medium with and without oleic acid (a long-chain fatty acid commonly used in mycobacteria
culture media, and likely a carbon source during infection). This screening identified ndh and etfD transposon
mutants as being sensitive to oleic acid, which is consistent with our previous findings. In this proposal we will
do a “deep dive” on the physiological function of the top hit of our Tn-seq screening. Preliminary data indicates
that an interplay between cAMP signaling, fatty acid catabolism and respiration impacts Mtb drug susceptibility
and pathogenicity. Understanding how these different cell processes interact will not only lead to a better
understanding of the pathogen’s biology, but it will unveil new strategies to sterilize Mtb infections.

## Key facts

- **NIH application ID:** 10739820
- **Project number:** 5R21AI168506-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** SABINE EHRT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $254,250
- **Award type:** 5
- **Project period:** 2022-11-14 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10739820

## Citation

> US National Institutes of Health, RePORTER application 10739820, Turning Mycobacterium tuberculosis appetite for fatty acids against itself (5R21AI168506-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10739820. Licensed CC0.

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