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Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione
Author(s) -
Lu Jun,
VlamisGardikas Alexios,
Kandasamy Karuppasamy,
Zhao Rong,
Gustafsson Tomas N.,
Engstrand Lars,
Hoffner Sven,
Engman Lars,
Holmgren Arne
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-223305
Subject(s) - ebselen , thioredoxin reductase , thioredoxin , glutaredoxin , glutathione , bacteria , glutathione reductase , microbiology and biotechnology , biochemistry , reductase , escherichia coli , chemistry , biology , enzyme , glutathione peroxidase , gene , genetics
Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH plays critical roles in cellular DNA synthesis and defense against oxidative stress. Notably, TrxR is very different in structure and mechanism in mammals and bacteria. Ebselen [2‐phenyl‐1,2 benzisoselenazol‐3(2 H )‐one], a well‐known antioxidant and a substrate for mammalian TrxR and Trx, is rapidly bacteriocidal for methicillin‐resistant Staphylococcus aureus by an unknown mechanism. We have discovered that ebselen is a competitive inhibitor of Escherichia coli TrxR with a K i of 0.52 ± 0.13 μM, through reaction with the active site dithiol of the enzyme. Bacteria lacking glutathione (GSH) and glutaredoxin, in which TrxR and Trx are essential for DNA synthesis, were particularly sensitive to ebselen. In growth‐inhibited E. coli strains, Trx1 and Trx2 were oxidized, demonstrating that electron transfer via thioredoxin was blocked. Ebselen and its sulfur analog ebsulfur were bactericidal for GSH‐negative pathogens. Ebsulfur inhibited a clinically isolated Helicobacter pylori strain with a minimum inhibitory concentration value as low as 0.39 μg/ml. These results demonstrate that bacterial Trx and TrxR are viable antibacterial drug targets using benzisoselenazol and benzisothiazol derivates.—Lu, J., Vlamis‐Gardikas, A., Kandasamy, K., Zhao, R., Gustafsson, T. N., Engstrand, L., Hoffner, S., Engman, L., Holmgren, A. Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione. FASEB J. 27, 1394–1403 (2013). www.fasebj.org