Bacterial thioredoxin reductase inhibitors and methods for...

Details Bacterial thioredoxin reductase inhibitors and methods for... Bacterial thioredoxin reductase inhibitors and methods for...

A - Human Necessities

61

K

A61K 31/41 (2006.01) A61K 31/4439 (2006.01) A61P 31/04 (2006.01) A61P 31/06 (2006.01)

Patent

CA 2687451

The mechanism of action of Ebselen differentiates between bacterial and mammalian thioredoxin reductase (TrxR). It displays fast oxidation of mammalian Trx and via the NADPH-TrxR catalyzed turnover of ebselen selenol with hydrogen peroxide, and therefore are mammalian antioxidants. Ebselen, and its diselenide, are strong competitive inhibitors of E.coli TrxR with Ki of 0.14 µM and 0.46 µM, respectively. E.coli mutants lacking glutathione reductase or glutathione were much more sensitive to inhibition by ebselen. Since either glutaredoxin or thioredoxin systems are electron donors to ribonucleotide reductase, ebselen targets primarily glutathione and glutaredoxin-negative bacteria, a class which includes major pathogens. Ebselen, and similar compounds are therefore useful as antibacterial agents, even for multiresistant strains. Two major pathogenic bacteria, which previously had not been known to be sensitive to ebselen, Mycobacterium tuberculosis (tuberculosis) and Helicobacter pylori (stomach ulcer and cancer), were shown to be excellent targets. Helicobacter pylori was also sensitive to ebsulfur.

Le mécanisme d'action d'e l'ebselen se différencie de la éductase thioredoxine mammalienne et bactérienne (TrxR). Il affiche une oxydation rapide de Trx et via la rotation catalysée NADPH-TrxR de sélénol d'ebselen avec du péroxyde d'hydrogèneet ainsi constituen des antioxydants mammaliens. L'ebselen et son diséléniure sont de forts inhibiteurs compétitifs de E.coli TrxR avec Ki de 0.14 µM et 0.46 µM, respectivement. Les mutants E.coli privés de réductase de glutathione ou de glutathione étaient beaucoup plus sensibles à l'inhibition par l'ebselen. Etant donné que les systèmes de glutaredoxine ou de thioredoxine sont des donneurs d'électron pour la réductase de ribonucléotide, l'ebselen vise principalement les bactéries de glutathione et les bactéries négatives de glutaredoxine, une classe qui comprend les principaux pathogènes. L'ebselent et d'autres composés similaires sont ainsi utiles comme agents antibactériens, même pour des souches multirésistantes. Deux bactéries pathogènes majeures, qui n'étaient auparavant pas connues pour être sensibles à l'ebselen, Mycobacterium tuberculosis (tuberculose) et Helicobacter pylori (ulcère de l'estomac et cancer) se sont révélées être d'excellentes cibles. Helicobacter pylori est également sensible à l'ebsoufre.

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