# Chemical disarming of drug resistance in Mycobacterium tuberculosis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $663,411

## Abstract

PROJECT SUMMARY/ABSTRACT
Antibiotic resistant infections are a dangerous, worldwide health problem. Chief among these pathogens is
Mycobacterium tuberculosis (Mtb), which causes an estimated 1.5 million deaths a year. The emergence of
drug-resistant Mtb strains, which constitute 20% of previously treated tuberculosis (TB) cases, has
exacerbated this already alarming epidemic. The inadequacies of present TB therapies demand the discovery
of new agents with unique mechanisms of action to treat Mtb infection. Towards this end, we have discovered
and developed a new family of compounds (termed Mycobacterial Tolerance Inhibitors, MTIs) that potently
sensitize Mtb to stresses encountered during infection as well as to the frontline antibiotic isoniazid (INH). In
addition, we show that combining MTIs with INH blocks the selection for INH-resistance and restores INH
activity in otherwise INH-resistant Mtb isolates. To the best of our knowledge, MTIs are the first report of
compounds that block INH resistance and re-sensitize INH-resistant bacteria to INH. INH is included in the
standard of care (SOC) regimens for both prophylactic treatment of latent TB as well as treatment of active TB.
Unfortunately, the increase in INH-resistant cases of TB is threatening the relevance of this antibiotic, which
would generate a large gap in our treatment options. MTIs represent an innovative strategy for combating TB
drug resistance. In preliminary mechanistic work, we show that MTIs induce expression profiles and changes
in physiology that are indicative of dysregulation of respiration. Therefore, we hypothesize that MTIs modulate
respiration in Mtb, leading to sensitization to stresses associated with respiration, potentiation of INH activity,
and re-sensitization of INH-resistant mutants to INH, which will all improve the efficacy of antibiotic therapy and
immune responses during infection. We have demonstrated that MTIs have pharmacokinetic (PK) properties
suitable for oral dosing, further supporting their promise for translation to treatments in humans. Our short-term
objectives are to demonstrate preclinical proof-of-concept for MTIs to combat Mtb infection, optimize the
current lead MTIs for translation to a therapeutic, and reveal new insights into pathways of drug tolerance and
resistance. Our long-term objective is to develop a new orally available antibiotic that improves the current
SOC regimens for patients with drug-sensitive and resistant TB. Using our combined expertise in chemistry
and Mtb biology, we will achieve our objectives by addressing the following independent aims: 1) Optimize
MTIs through structure-activity relationships (SAR) and structure-property relationships (SPR) studies. 2)
Dissect the exact mode of action and the detailed mechanisms by which MTIs impact INH and stress
sensitivity. 3) Determine the activity of MTIs during Mtb infection. Successful completion of these aims will
result in the development of an innovative therapeutic str...

## Key facts

- **NIH application ID:** 10190796
- **Project number:** 5R01AI134847-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Fredrik Almqvist
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $663,411
- **Award type:** 5
- **Project period:** 2018-07-16 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190796

## Citation

> US National Institutes of Health, RePORTER application 10190796, Chemical disarming of drug resistance in Mycobacterium tuberculosis (5R01AI134847-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10190796. Licensed CC0.

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