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.

Public Health Relevance

Tuberculosis is the leading cause of death world-wide from an infectious disease, fueled by its synergy with the HIV pandemic. This crisis is escalating due to the rise in drug resistant tuberculosis, driving the urgent need for new antibiotics. The goal of this work is to address this need by the development of a promising new candidate with demonstrated in vivo, orally bioavailable efficacy in animal models.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1)
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Boyce, Jim P
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Broad Institute, Inc.
United States
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Fang, Chao; Lee, Katie K; Nietupski, Raymond et al. (2018) Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors. Bioorg Med Chem Lett 28:3529-3533