Abstract
Cytochrome bd-type oxidases play a crucial role for survival of pathogenic bacteria during infection and proliferation. This role and the fact that there are no homologues in the mitochondrial respiratory chain qualify cytochrome bd as a potential antimicrobial target. However, few bd oxidase selective inhibitors have been described so far. In this report, inhibitory effects of Aurachin C (AurC-type) and new Aurachin D (AurD-type) derivatives on oxygen reductase activity of isolated terminal bd-I, bd-II and bo3 oxidases from Escherichia coli were potentiometrically measured using a Clark-type electrode. We synthesized long- (C10, decyl or longer) and short-chain (C4, butyl to C8, octyl) AurD-type compounds and tested this set of molecules towards their selectivity and potency. We confirmed strong inhibition of all three terminal oxidases for AurC-type compounds, whereas the 4(1H)-quinolone scaffold of AurD-type compounds mainly inhibits bd-type oxidases. We assessed a direct effect of chain length on inhibition activity with highest potency and selectivity observed for heptyl AurD-type derivatives. While Aurachin C and Aurachin D are widely considered as selective inhibitors for terminal oxidases, their structure–activity relationship is incompletely understood. This work fills this gap and illustrates how structural differences of Aurachin derivatives determine inhibitory potency and selectivity for bd-type oxidases of E. coli.
Highlights
Cytochrome bd-type oxidases play a crucial role for survival of pathogenic bacteria during infection and proliferation
Binding of the aurachin derivative AD5-10 results in decrease of oxygen reductase activity in the wild-type control in accordance with spectral shifts only for heme b-558
Specific protein inhibitors can be of use as antibiotically active compounds, and as binding ligands to enable deeper investigations of protein mechanisms
Summary
Cytochrome bd-type oxidases play a crucial role for survival of pathogenic bacteria during infection and proliferation. Inhibitory effects of Aurachin C (AurC-type) and new Aurachin D (AurD-type) derivatives on oxygen reductase activity of isolated terminal bd-I, bd-II and bo[3] oxidases from Escherichia coli were potentiometrically measured using a Clarktype electrode. Experiments with the multidrug efflux transporter deficient TolC strain of Escherichia coli (E. coli) showed a moderate antibacterial effect of AurD (farnesyl) and two derivative variants with geranyl and prenyl isoprenoid side chain These results raised hopes that this group of compounds may serve as a new antibiotic class in the future[4]. E. coli encodes for three terminal membrane-integrated oxygen reductases: cytochromes bd-I, bd-II and bo[3] All of these terminal oxidases contribute to the generation of an electrochemical proton gradient (proton motive force) across the cytoplasmic membrane which is the driving force for ATP synthesis of and secondary active transport. Functional assays on purified protein with a diverse set of quinolones enabled us to identify structural features that determine selectivity and potency
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