CHARACTERIZATION OF GLUTATHIONE PEROXIDASE MIMICRY-LINKED THERAPEUTIC MECHANISM OF DIPHENYL DISELENIDE IN STAPHYLOCOCCUS AUREUS -MEDIATED SYSTEMIC DYSFUNCTION

Abstract

The in vitro glutathione peroxidase mimicry of diphenyl diselenide (DPDSe) has been linked to the oxidation of non-protein and protein thiols suggesting that its pharmacology is integrally linked to its toxicity. Considering the fact that Staphylococcus aureus (S. aureus) is sensitive to DPDSe, it is not clear if its antibacterial mechanism involves thiol modulation, hence necessitating this study. Herein, the in vitro sensitivity of S. aureus to DPDSe was tested and this was followed by estimating the minimum inhibitory and bactericidal concentrations [MIC and MBC respectively] of DPDSe on the growth of the S. aureus. In addition, the effect of thiols [dithiothreitol (DTT), cysteine (CYS) and reduced glutathione (GSH)] and thiol modifiers (iodoacetamide and diamide) either or in combination with DPDSe were tested on the growth of the S. aureus. Also, the possible inhibitory effect of DPDSe on the activities of some thiol containing enzymes [such as sodium pump, delta aminolevulinic acid dehydratase and the purinergic enzymes, 5’-nucleotidase and nucleoside triphosphate diphosphohydrolase (NTPDase)] found in S. aureus were determined as a likely component of its antibacterial action against S. aureus. Ultimately, the antibacterial action of DPDse was also tested in an in vivo model of S. aureus infected rats. Apparently, DPDSe markedly inhibited the growth of S. aureus with MIC and MBC of 800 and 1000μM respectively. Moreso, thiols (CYS, GSH and DTT) or in combination with DPDSe profoundly prevented and reversed the inhibitory effect of DPDSe on the growth of S. aureus. Furthermore, DPDSe markedly inhibited the activities of the thiol-containing enzymes tested in the S. aureus. Finally, DPDSe restored disturbed redox status and activities of sulphydryl enzymes in albino rats previously infected with S. aureus. It appears that the formation of selenol-derivatives of DPDSe via its GPx mimicry may account for its observed antibacterial effect against S. aureus. Consequently, since formation of selenol-derivatives of DPDSe is not dependent on the strict fidelity towards any protein thiol, thus DPDSe holds promise as a medicament in the management of antibiotics resistance strains of S. aureus.