Thienothiazolocarboxamides: rapidly cidal agents causing catastrophic thiol collapse in Mycobacterium tuberculosis.
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
- Kirsteen I. Buchanan
- José Santinni Roma
- Laura A. T. Cleghorn (ORCID: https://orcid.org/0000-0001-6218-0092)
- Paul Graham Wyatt (ORCID: https://orcid.org/0000-0002-0397-245X)
- Clifton E. Barry (ORCID: https://orcid.org/0000-0002-2927-270X)
- Ashish Kumar (ORCID: https://orcid.org/0000-0002-1733-2955)
- Neha Quadir (ORCID: https://orcid.org/0000-0002-4900-8172)
- Helena I. Boshoff (ORCID: https://orcid.org/0000-0002-4333-206X)
- Thomas R. Ioerger (ORCID: https://orcid.org/0000-0001-8702-9102)
- Jansy Passiflora Sarathy (ORCID: https://orcid.org/0000-0002-1532-146X)
- Simon R. Green (ORCID: https://orcid.org/0000-0001-5054-4792)
- Nilesh Mukundan (ORCID: https://orcid.org/0000-0002-8928-4809)
- Peter C. Ray (ORCID: https://orcid.org/0000-0002-7828-0853)
- Adrian L. Schwan (ORCID: https://orcid.org/0000-0003-3362-9633)
- Sangmi Oh
- Gareth Prosser
- Sarah Hanson
Institutions
- University of Dundee (GB)
- National Institute of Allergy and Infectious Diseases (US)
- National Institute of Research in Tuberculosis (IN)
- Hackensack Meridian Health (US)
- University of Guelph (CA)
- Texas A&M University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-11-09
- DOI
- https://doi.org/10.64898/2026.11.06.764870
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- preprint