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PRODID:-//University of Otago//Events Calendar//EN
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UID:https://www.otago.ac.nz/news/events/biochemistry-seminar-tianyu-zhang
URL:https://www.otago.ac.nz/news/events/biochemistry-seminar-tianyu-zhang
DTSTART;TZID=Pacific/Auckland:20260908T120000
DTEND;TZID=Pacific/Auckland:20260908T130000
SUMMARY:Biochemistry seminar: Tianyu Zhang
DESCRIPTION:Enoyl-acyl carrier protein reductase (InhA) is essential for the synthesis of the Mycobacterium tuberculosis (Mtb) cell wall and is the molecular target of the first-line anti-tuberculosis drug isoniazid (INH). However, high rates of INH resistance—primarily driven by mutations in the pro-drug activating enzyme KatG, rather than in InhA itself and the high toxicity—have severely limited its utility. Despite extensive efforts to develop direct InhA inhibitors (DIIs), most candidates have demonstrated potent antimycobacterial activity but lack the physicochemical and pharmacokinetic properties required for clinical advancement. Here, we report W14, a preclinical DII candidate that exhibits potent activity against both multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical Mtb isolates. Notably, W14 demonstrates the highest efficacy among reported DIIs in orally treated murine tuberculosis models. In novel combination regimens, W14 significantly outperforms INH in reducing bacterial burden and preventing relapse. W14 displays excellent oral bioavailability, a prolonged half-life, and low toxicity in preliminary preclinical assessments. Resistance mapping reveals that W14-resistant mutants containing mutations exclusively within the inhA gene or its promoter—distinct from the resistance pattern even in inhA associated with INH. These findings position W14 as a promising candidate for inclusion in next-generation anti-tuberculosis regimens, with the potential to enhance therapeutic efficacy and mitigate resistance development, warranting its advancement into clinical development. 
LOCATION:Biochemistry Seminar Room G.13 (BIG13), 710 Cumberland Street, Dunedin
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