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Sökning: onr:"swepub:oai:DiVA.org:uu-198514" > Inhibition of Bacte...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00003441naa a2200397 4500
001oai:DiVA.org:uu-198514
003SwePub
008130417s2013 | |||||||||||000 ||eng|
009oai:prod.swepub.kib.ki.se:126477672
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1985142 URI
0247 a https://doi.org/10.1096/fj.12-2233052 DOI
0247 a http://kipublications.ki.se/Default.aspx?queryparsed=id:1264776722 URI
040 a (SwePub)uud (SwePub)ki
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Lu, Junu Karolinska Institutet4 aut
2451 0a Inhibition of Bacterial Thioredoxin Reductase: An Antibiotic Mechanism Targetting Bacteria Lacking Glutathione
264 c 2012-12-17
264 1b Wiley,c 2013
338 a print2 rdacarrier
520 a  Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxinreductase (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(2H)-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 mu M, 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 mu g/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. 
7001 a Vlamis-Gardikas, Alexiosu Karolinska Institutet4 aut
7001 a Kandasamy, Karuppasamyu Karolinska Institutet4 aut
7001 a Zhao, Rongu Karolinska Institutet4 aut
7001 a Gustafsson, Tomasu Karolinska Institutet4 aut
7001 a Engstrand, Larsu Karolinska Institutet4 aut
7001 a Hoffner, Svenu Karolinska Institutet4 aut
7001 a Engman, Larsu Uppsala universitet,Syntetisk organisk kemi4 aut0 (Swepub:uu)len21181
7001 a Holmgren, Arneu Karolinska Institutet4 aut
7102 a Karolinska Institutetb Syntetisk organisk kemi4 org
7730 t The FASEB Journald : Wileyg 27:4, s. 1394-1403q 27:4<1394-1403x 0892-6638x 1530-6860
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-198514
8564 8u https://doi.org/10.1096/fj.12-223305
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:126477672

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