Thiazolino-Pyridone Compounds as Novel Antimycobacterial Drugs for Tuberculosis

Project Summary/Abstract Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), is a leading cause of global mortality, due to infection. In 2022, ~10.6 million people were newly diagnosed with TB and 1.3 million people died from the disease. As efforts to treat TB expand, the prevalence of infections caused by drug-resistant Mtb is increasing; in part due to the long duration (6 months) of combination therapy (4 antibiotics) for drug- strains (DR-TB) that are resistant to one or more frontline standard of care (SoC) antibiotics, sensitive TB (DS-TB), which leads to poor compliance. Treatment for DR-TB is even longer (typically ranging from 6-24 months), with 3, 4, or more, antibiotics taken in combination. Despite the recent discovery and approval of several TB drugs, including bedaquiline (BDQ), resistance is already emerging. Therefore, new classes of drugs, with new mechanisms of action (MoAs), that can be combined with new or existing TB drugs, are desperately needed. The success of BDQ, which disrupts energy metabolism in Mtb and is a component of new drug regimens for DR-TB that reduce treatment times and improve outcomes, has accompanied an explosion of drug discovery targeting respiration in Mtb. In this application, Fimbrion proposes to develop an orally bioavailable, thiazolino-pyridone (TZP) small molecule series, with inhibitory activity against Mtb, as a novel drug for treating TB. While the target of this compound series is currently unknown, TZPs appear to act through disruption of Mtb respiration. Importantly, TZPs have the added property of potentiating isoniazid (INH) activity (a key frontline TB antibiotic), against both INH-sensitive and INH-resistant Mtb in vitro; restoring activity against the latter and reducing the emergence of INH resistance. Our project goal is to develop a first- in-class TZP compound that could become part of a shortened, INH-containing drug regimen, that effectively treats both DS- and DR-TB. In vitro, we have shown that exemplars of the TZP series have variable potency, stability, solubility, and safety, with several lead compounds have demonstrated promising pharmacokinetic (PK) profiles, with good oral potency leads tending to have poor solubility and/or cellular toxicity. In vivo, bioavailability (%F) and half-lives in mice, however these compounds have lacked the potency necessary for establishing proof-of-principle (PoP) in vivo efficacy. Herein, we propose to 1) optimize and balance the potency, safety, and drug-like properties of the TZP series, using medicinal chemistry strategies and SAR feedback from biological assays, to identify an advanced lead series of TZPs suitable for PoP efficacy studies, and 2) assay prioritized lead compounds: i) in vitro for activity against diverse Mtb strains and under diverse clinically relevant conditions, and ii) in vivo for dose escalation PK and efficacy in a mouse model of acute TB. Upon completion of this project, we expect to have identified an advanced lead series of TZPs, with good potency, and physicochemical and PK properties capable of effectively treating TB in an animal model of Mtb infection, which could be further developed as part of a combination therapy for TB in a Phase II SBIR.