Thienothiazolocarboxamides: rapidly cidal agents causing catastrophic thiol collapse in Mycobacterium tuberculosis.

Oh, S.; Prosser, G.; Boshoff, H. I. M.; Green, S. R.; Quadir, N.; Roma, J. S. O.; Kumar, A.; Mukundan, N.; Hanson, S.; Sarathy, J. P.; Buchanan, K. I.; Ray, P. C.; Wyatt, P. G.; Ioerger, T. R.; Schwan, A. L.; Cleghorn, L. A. T.; Barry, C. E.

doi:10.64898/2026.11.06.764870

bioRxiv · 10.64898/2026.11.06.764870

Thienothiazolocarboxamides: rapidly cidal agents causing catastrophic thiol collapse in Mycobacterium tuberculosis.

Oh, S.·Prosser, G.·Boshoff, H. I. M.·Green, S. R.·Quadir, N.·Roma, J. S. O.·Kumar, A.·Mukundan, N.·Hanson, S.·Sarathy, J. P.·Buchanan, K. I.·Ray, P. C.·Wyatt, P. G.·Ioerger, T. R.·Schwan, A. L.·Cleghorn, L. A. T.·Barry, C. E.

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Abstract

Thienothiazolocarboxamides (TTCs) were discovered as a hit in a whole cell screen for new antituberculosis agents. These molecules were rapidly cidal under both replicating and non-replicating conditions and killed Mycobacterium tuberculosis (Mtb) in macrophages. The heterobicyclic core of this scaffold was essential for activity and resistance to these agents was mediated by loss of EthA, a flavin containing monooxygenase also responsible for the bioactivation of ethionamide. EthA-mediated activation of TTCs in whole cells was found to produce mycothiol adducts and RNAseq profiles revealed a mechanism of action identical to the fungal mycotoxins patulin and nidulalin A. EthA oxidizes the sulfur of the thiazole ring to create a relatively stable sulfenic acid that reacts with cellular thiols. This unique, replication-independent, mechanism suggests the possibility that these molecules may contribute significantly to shortening the duration of tuberculosis chemotherapy.

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Oh, S., Prosser, G., Boshoff, H. I. M., Green, S. R., Quadir, N., Roma, J. S. O., Kumar, A., Mukundan, N., Hanson, S., Sarathy, J. P., Buchanan, K. I., Ray, P. C., Wyatt, P. G., Ioerger, T. R., Schwan, A. L., Cleghorn, L. A. T., Barry, C. E.. 2026-11-09. Thienothiazolocarboxamides: rapidly cidal agents causing catastrophic thiol collapse in Mycobacterium tuberculosis.. https://doi.org/10.64898/2026.11.06.764870

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