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.