# Dual Targeting of Mtb Resistance Mechanisms

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $850,750

## Abstract

ABSTRACT
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, currently leads to nearly
1.7 million deaths a year. TB control is threatened by the continued emergence of drug-resistant Mtb strains.
Clinical resistance has now been observed against all TB drugs, underscoring the urgent need not just for new
drugs, but for entirely new strategies that directly target and disable drug resistance mechanisms. Two of the
most promising strategies to prevent the emergence of antibiotic resistance in the treatment of TB are the
targeting of drug tolerant, non-replicating bacterial populations and host-directed therapy (HDT). We identified a
series of drug-like ATP analogs with in vitro activity against replicating and non-replicating Mtb that is comparable
to that of rifampicin, one of the first-line drugs targeting non-replicating Mtb. Because these inhibitors were
originally developed for the inhibition of the human transforming growth factor receptor (TGFβR), a pathway
implicated in immunity to TB, we also sought to test whether inhibition of TGFβR mediates host-directed activity
against Mtb. We found that genetic deletion and chemical inhibition of TGFβR significantly reduced the bacterial
load in infected animals. We showed that T-cells lacking TGFβR had an increased capacity to interact in a
cognate manner with Mtb-infected macrophages and produce IFNγ at the pulmonary site of infection. These
preliminary studies suggest a new answer to the longstanding question why the T cell response to Mtb is
inadequate at the site of infection and highlights the possibility that TGFβ signaling is a new HDT target. Thus,
we identified compounds that have two independent activities that both kill Mtb and likely impede the emergence
of drug resistance. Using genetics and the ATP analogs as chemical tools, we will identify the cellular Mtb targets
responsible for directly killing Mtb, thus identifying new targets that underlie drug tolerance. On the host side, we
will determine the role of TGFβR signaling in Mtb infection. Lastly, we will test this dual host-pathogen targeting
strategy by testing the efficacy of our compounds in vivo.

## Key facts

- **NIH application ID:** 10095124
- **Project number:** 1R01AI158159-01
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Christoph Grundner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $850,750
- **Award type:** 1
- **Project period:** 2020-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10095124

## Citation

> US National Institutes of Health, RePORTER application 10095124, Dual Targeting of Mtb Resistance Mechanisms (1R01AI158159-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10095124. Licensed CC0.

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