# Heterocyclic Inhibitors of QcrB as Novel Drugs for Tuberculosis > **NIH NIH R44** · FIMBRION THERAPEUTICS, INC. · 2024 · $994,977 ## Abstract Project Summary/Abstract 1 Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), is a leading 2 cause of mortality due to infection, globally. In 2019, 10 million people were newly diagnosed with TB and 1.5 3 million people died from the disease. As efforts to treat TB expand, the prevalence of infections caused by 4 drug-resistant Mtb 5 is increasing, in part due to the long duration (6 months) of combination therapy (4 antibiotics) for drug-sensitve 6 TB (DS-TB), which results in poor compliance. Treatment for DR-TB is even longer, ranging from 6-24 months 7 typically, with 3, 4 or more antibiotics taken in combination. Despite the dire need for new treatments against 8 DR-TB, only one new antibiotic for TB with an entirely novel mechanism of action (MoA) has been approved in 9 the past 40 years, bedaquiline. Therefore, new classes of drugs with new MoAs that can be combined with 10 existing or new TB drugs in the pipeline are desperately needed. The success of bedaquiline, which disrupts 11 energy metabolism in Mtb and has shown promise in reducing treatment times for DR-TB, has accompanied 12 an explosion of drug discovery targeting respiration in Mtb. Fimbrion is developing a thienopyrimidine small 13 molecule series that targets the Mtb QcrB protein 14 electron transport chain in Mtb, has been validated as a drug target by the early clinical success of the QcrB 15 inhibitor, Q203, which is currently in Phase 2 clinical trials, but has potential liabilities. Our goal in this project is 16 to develop a best-in-class QcrB inhibitor that could become part of a shorter drug regimen that effectively treats 17 both DS- and DR-TB. Initially in our Phase I project, we had examples of some very potent compounds, but 18 metabolic stability was poor. Our Phase I goals, therefore, were to optimize stability, while maintaining or 19 improving potency, so that we could test lead compounds in an animal model of Mtb infection. We achieved 20 this goal, identifying a lead THP series of stable QcrB inhibitors with low nM potency, favorable PK properties, 21 including oral bioavailability, and demonstrated in vivo efficacy in a mouse model of acute TB infection. In our 22 Phase II project, we will optimize our lead series with the goal of identifying and de-risking a clinical candidate 23 molecule that is effective in treating TB. Specifically, we will 1) further optimize our lead series to improve drug- 24 like properties and pharmacokinetics, while maintaining or improving our current in vitro potency and in vivo 25 efficacy; 2) investigate: i) the efficacy of lead compounds against diverse Mtb stains and under clinically 26 relevant conditions, ii) the risk of resistance, iii) potential in vitro synergy with other anti-Mtb drugs, and iv) in 27 vitro toxicity and potential adverse drug-drug interactions; and 3) test advanced lead compounds for efficacy in 28 clinically relevant mouse models of TB disease and ass... ## Key facts - **NIH application ID:** 10735871 - **Project number:** 5R44AI149833-05 - **Recipient organization:** FIMBRION THERAPEUTICS, INC. - **Principal Investigator:** THOMAS Joseph HANNAN - **Activity code:** R44 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $994,977 - **Award type:** 5 - **Project period:** 2019-12-13 → 2024-11-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10735871 ## Citation > US National Institutes of Health, RePORTER application 10735871, Heterocyclic Inhibitors of QcrB as Novel Drugs for Tuberculosis (5R44AI149833-05). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10735871. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*