Thienothiazolocarboxamides: rapidly cidal agents causing catastrophic thiol collapse in Mycobacterium tuberculosis.
Year: 2026
Type: preprint
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.
Authors: Sangmi Oh, Gareth Prosser, Helena I.M. Boshoff, Simon Richard Green, Neha Quadir, Jose Santinni O. Roma, Ashish Kumar, Nilesh Mukundan, Sarah Hanson, Jansy Passiflora Sarathy, Kirsteen I Buchanan, Peter C. Ray, Paul G. Wyatt, Thomas R. Ioerger, Adrian L. Schwan, Laura A.T. Cleghorn, Clifton E. Barry
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225621600
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