Inhibition of bacterial disulfide bond formation by the anticoagulant warfarin
- 29 December 2009
- journal article
- Published by National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 107 (1) , 297-301
Abstract
Blood coagulation in humans requires the activity of vitamin K epoxide reductase (VKOR), the target of the anticoagulant warfarin (Coumadin). Bacterial homologs of VKOR were recently found to participate in a pathway leading to disulfide bond formation in secreted proteins of many bacteria. Here we show that the VKOR homolog from the bacteriumMycobacterium tuberculosis, the causative agent of human tuberculosis, is inhibited by warfarin and that warfarin-resistant mutations of mycobacterial VKOR appear in similar locations to mutations found in human patients who require higher doses of warfarin. Deletion of VKOR results in a severe growth defect in mycobacteria, and the growth ofM. tuberculosisis inhibited by warfarin. The bacterial VKOR homolog may represent a target for antibiotics and a model for genetic studies of human VKOR. We present a simple assay inEscherichia coli, based on a disulfide-sensitive β-galactosidase, which can be used to screen for stronger inhibitors of theM. tuberculosisVKOR homolog.Keywords
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