Design, Synthesis, and Evaluation of Novel Δ<sup>2</sup>-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant <i>Mycobacterium tuberculosis</i> Mutant
Souvik Sarkar, Anne E. Mayer Bridwell, James A. D. Good, Erin R. Wang, Samuel R. McKee, Joy C. Valenta, Gregory A. Harrison, Kelly Flentie, Frederick L. Henry, Torbjörn Wixe, Peter Demirel, Siva K. Vagolu, Jonathan Chatagnon, Arnaud Machelart, Priscille Brodin, Tone Tønjum, Christina L. Stallings, Fredrik Almqvist
Abstract
High Resolution Image Download MS PowerPoint Slide Mycobacterium tuberculosis ( Mtb ) drug resistance poses an alarming threat to global tuberculosis control. We previously reported that C10, a ring-fused thiazolo-2-pyridone, inhibits Mtb respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant Mtb isolates. This discovery revealed a new strategy to address INH resistance. Expanding upon this strategy, we identified C10 analogues with improved potency and drug-like properties. By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold, we identified two novel isoxazoles, 17h and 17j . 17h and 17j inhibited Mtb respiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant Mtb mutant, and more effectively inhibited intracellular Mtb replication than C10 . The (−)17j enantiomer showed further enhanced activity compared to its enantiomer and the 17j racemic mixture. Our potent second-generation C10 analogues offer promise for therapeutic development against drug-resistant Mtb .