# Preclinical evaluation of compounds that inhibit cholesterol uptake in M. tuberculosis.

> **NIH NIH R01** · CORNELL UNIVERSITY · 2020 · $440,175

## Abstract

Project Summary / Abstract
 Cholesterol metabolism in Mtb is an attractive target for basic research and new drug development efforts.
The Mtb cholesterol metabolic pathway is specific to the bacteria and mutants defective in this pathway are
attenuated in various infection models. This suggests that chemically inhibiting this pathway will also attenuate
Mtb virulence in vivo. We recently discovered a compound series that blocks cholesterol uptake in Mtb and
stimulates cAMP overproduction in the bacteria. This is important since cAMP regulates mycobacterial central
metabolism, transcription, pathogenicity, dormancy, and stress responses. Thus, chemically stimulating cAMP
production in Mtb will perturb multiple different aspects of bacterial physiology in addition to cholesterol utilization.
 Granulomas are a major pathologic barrier that limits immune cell recruitment and antibiotic diffusion. Within
a granuloma Mtb is sequestered in a cholesterol rich and hypoxic microenvironment that is thought to favor
bacterial persistence. During infection, MΦ’s produce TNF-α which drives TB tissue pathology and is required to
form and maintain granulomas. It is thought that TNF-α depletion can disturb the granuloma architecture and
promote enhanced antibiotic availability or disrupt the granuloma microenvironment making TB antibiotics more
effective. It has long been known that TNF-α production by MΦ’s can be down regulated in response to high
levels of cytosolic cAMP and it is also known that Mtb-derived cAMP down regulates TNF-α production in MΦ’s.
Our compound series stimulates enough Mtb-derived cAMP to down regulate TNF-α production at the infected
cell level. Thus, stimulating cAMP overproduction in Mtb could be a novel strategy to reduce TNF-α levels
specifically in infected MΦ’s to enhance the activity of current TB drugs.
 Here we propose to characterize the molecular mechanisms of how these probes block cholesterol uptake
and stimulate the overproduction of cAMP in Mtb (Aim 1). We also will determine how Mtb-derived cAMP
modulates: (i) the host immune response, (ii) MΦ function, and (iii) evaluate the efficacy of V-59 alone and in
combination with known TB antibiotics in vivo with a goal of evaluating the therapeutic potential of V-59 (Aim 2).
Because we already have a compound that has excellent potency and demonstrates in vivo efficacy via the oral
route, we are well positioned to make progress with a potential TB drug candidate and novel treatment strategy.

## Key facts

- **NIH application ID:** 9986645
- **Project number:** 5R01AI130018-04
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Brian C VanderVen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $440,175
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986645

## Citation

> US National Institutes of Health, RePORTER application 9986645, Preclinical evaluation of compounds that inhibit cholesterol uptake in M. tuberculosis. (5R01AI130018-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9986645. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*