# New targets against tuberculosis

> **NIH NIH R01** · BROAD INSTITUTE, INC. · 2020 · $1,080,104

## Abstract

ABSTRACT
 Tuberculosis is the leading causes of death by infectious diseases worldwide, having recently surpassed
HIV and killing an estimated 1.4 million people annually. Drug resistant tuberculosis is becoming an increasing
problem, including the recent emergence of strains that have been designated “totally drug resistant,” with
relatively few options in the drug development pipeline to combat this crisis. The problem of drug resistance is
now posing a serious threat to the management of TB and human health. Increased efforts are urgently needed
to identify new therapeutic candidates that are active against drug resistant Mycobacterium tuberculosis.
 To address this need, we propose to advance a novel chemical class of compounds, 4,6-diaryl substituted
quinolines that we have designed to target M. tuberculosis by a new mechanism of action. Importantly, we have
demonstrated that this class has excellent in vivo animal efficacy against TB when administered once-a-day and
orally, a barrier passed by very few molecules at the discovery stage. In fact, the lead candidate has an ED50 in
infected mice of 4.9 mg/kg, which makes it on par with some of the most potent current anti-tubercular drugs.
These substituted quinolines are bactericidal against M. tuberculosis by inhibiting the enzymatic function of a
new target, FadD32, for which there is no human homologue. Importantly, Fad32 is an essential enzyme in
mycolic acid biosynthesis, a well-validated pathway for therapeutic targeting as illustrated by the prominent role
played by another inhibitor of this pathway, isoniazid, in current TB therapy. New molecules that hit novel targets
in validated pathways have the dual advantage of a high likelihood of therapeutic efficacy based on a proven
mechanism of action while overcoming the high levels of resistance to current inhibitors of the pathway. Given
that it has been extremely challenging to translate animal to human efficacy, inhibiting pathways or functions that
have successfully been targeted by current TB therapy increases the likelihood of successful translation.
 One of the major hurdles to the successful translation of basic discovery research has been the gap
between the initial basic research discovery and therapeutic development. We propose to develop the 4,6-diaryl
quionlines in a seamless, interdisciplinary collaboration between leading academic scientists and industry
professionals, all who have worked together previously, who will span the disciplines of TB biology, biochemistry,
structural biology, medicinal chemistry, and pre-clinical PK/ADME/toxicity in order to progress this promising
candidate through the preclinical development of TB therapeutics, from lead optimization to IND filing.

## Key facts

- **NIH application ID:** 9933801
- **Project number:** 5R01AI132300-04
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** DEBORAH T HUNG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,080,104
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933801

## Citation

> US National Institutes of Health, RePORTER application 9933801, New targets against tuberculosis (5R01AI132300-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933801. Licensed CC0.

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