Covalent Modification of the FAS-II Dehydratase by Isoxyl and Thiacetazone

Overview

Journal ACS Infect Dis

Specialties Infectious Diseases
Microbiology
Pharmacology

Date 2015 Apr 22

PMID 25897434

Citations 20

Authors

Anna E Grzegorzewicz

Nathalie Eynard

Annaik Quemard

E Jeffrey North

Alyssa Margolis

Jared J Lindenberger

Victoria Jones

Jana Kordulakova

Patrick J Brennan

Richard E Lee

Donald R Ronning

Michael R McNeil

Mary Jackson

Affiliations

Soon will be listed here.

Abstract

Isoxyl and Thiacetazone are two antitubercular prodrugs formerly used in the clinical treatment of tuberculosis. Although both prodrugs have recently been shown to kill through the inhibition of the dehydration step of the type II fatty acid synthase pathway, their detailed mechanism of inhibition, the precise number of enzymes involved in their activation and the nature of their activated forms remained unknown. We here demonstrate that both Isoxyl and Thiacetazone specifically and covalently react with a cysteine residue (Cys61) of the HadA subunit of the dehydratase thereby inhibiting HadAB activity. Our results unveil for the first time the nature of the active forms of Isoxyl and Thiacetazone and explain the basis for the structure-activity relationship of and resistance to these thiourea prodrugs. Our results further indicate that the flavin-containing monooxygenase EthA is most likely the only enzyme required for the activation of ISO and TAC in mycobacteria.

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