Thienothiazolocarboxamides: rapidly cidal agents causing catastrophic thiol collapse in Mycobacterium tuberculosis.
- 1Tuberculosis Research Section, LCID, NIAID, NIH
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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BibTeX
@misc{oh2026thienothiazolocarboxamides,
title = {{Thienothiazolocarboxamides: rapidly cidal agents causing catastrophic thiol collapse in Mycobacterium tuberculosis.}},
author = {S. Oh and G. Prosser and H. I. M. Boshoff and S. R. Green and N. Quadir and J. S. O. Roma and A. Kumar and N. Mukundan and S. Hanson and J. P. Sarathy and K. I. Buchanan and P. C. Ray and P. G. Wyatt and T. R. Ioerger and A. L. Schwan and L. A. T. Cleghorn and C. E. Barry},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.764870},
url = {https://www.biorxiv.org/content/10.64898/2026.11.06.764870v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Thienothiazolocarboxamides: rapidly cidal agents causing catastrophic thiol collapse in Mycobacterium tuberculosis.
AU - S. Oh
AU - G. Prosser
AU - H. I. M. Boshoff
AU - S. R. Green
AU - N. Quadir
AU - J. S. O. Roma
AU - A. Kumar
AU - N. Mukundan
AU - S. Hanson
AU - J. P. Sarathy
AU - K. I. Buchanan
AU - P. C. Ray
AU - P. G. Wyatt
AU - T. R. Ioerger
AU - A. L. Schwan
AU - L. A. T. Cleghorn
AU - C. E. Barry
PY - 2026
DA - 2026/11/06
PB - bioRxiv
DO - 10.64898/2026.11.06.764870
UR - https://www.biorxiv.org/content/10.64898/2026.11.06.764870v1
AB - 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.
ER -