# Heterocyclic Inhibitors of QcrB as Novel Drugs for Tuberculosis

> **NIH NIH R43** · FIMBRION THERAPEUTICS, INC. · 2021 · $293,050

## Abstract

Tuberculosis (TB) is caused by infection with the bacterium Mycobacteria tuberculosis (Mtb) and is the leading
cause of mortality in the world for a single infectious agent. As efforts to treat TB expand, the prevalence of
multidrug resistant TB (MDR-TB), which are resistant to the frontline standard of care (SOC) antibiotics
rifampicin and isoniazid, is increasing. Despite the dire need for new treatments against drug resistant TB, only
one new class of antibiotics has made it into the clinic for treatment of MDR-TB in the past 40 years and the
approved drug from this class, bedaquiline, has significant side effects, including death. Therefore, new
classes of drugs that target Mtb in ways that synergize with existing drug sensitive TB and MDR-TB SOC
therapies are desperately needed. To this end, Fimbrion has in-licensed the intellectual property for a series of
heterocyclic compounds with inhibitory and bactericidal activity against Mtb in vitro. This technology originated
at Washington University and Saint Louis University, and the most potent members of these series have
activity at inhibitor concentrations (IC50) in the low nanomolar range. The target of this compound series is the
QcrB protein, a component of the respiratory electron transport chain in Mtb, suggesting that these compounds
inhibit Mtb growth and survival through disrupting respiration. QcrB has recently been identified as a viable
drug target for treating TB, but our compound series has a unique structure compared to the one QcrB
inhibitor, Q203, that is currently in clinical trials and our compounds have bactericidal activity in vitro, whereas
bactericidal activity has not been reported for Q203. While many physiochemical properties of this scaffold are
suitable for drug development and we have generated some very potent compounds, low metabolic stability
has thus far been a liability. Therefore, optimizing stability, while maintaining potency, will be a priority of our
chemical optimization efforts. The main goal or our project proposal is to develop a lead series of novel
heterocyclic QcrB inhibitors with improved pharmacokinetic (PK) properties that will be capable of effectively
treating TB in an animal model of Mtb infection. To achieve this goal, we will expand our library of compounds,
focusing on two subclasses of heterocycles in order to discover and optimize candidate lead series with
increased metabolic stability, while maintaining potency and minimizing cellular toxicity. To properly direct lead
series identification and optimization, we will select early lead compounds initially and then later optimized lead
series compounds with high potency and increased stability for in vivo PK. Candidate leads with favorable PK
profiles will be tested for in vitro activity against a collection of 10 diverse drug-sensitive and MDR Mtb strains
as well as for synergy with bedaquiline, which also targets Mtb respiration. We will then perform proof of
principle experiments to tes...

## Key facts

- **NIH application ID:** 10071132
- **Project number:** 5R43AI149833-02
- **Recipient organization:** FIMBRION THERAPEUTICS, INC.
- **Principal Investigator:** THOMAS Joseph HANNAN
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $293,050
- **Award type:** 5
- **Project period:** 2019-12-13 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071132

## Citation

> US National Institutes of Health, RePORTER application 10071132, Heterocyclic Inhibitors of QcrB as Novel Drugs for Tuberculosis (5R43AI149833-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10071132. Licensed CC0.

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