Short-chain aurachin D derivatives are selective inhibitors of E. coli cytochrome bd-I and bd-II oxidases

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.

Synthesis and Biological Evaluation of Aurachin D Analogues as Inhibitors of Mycobacterium tuberculosis Cytochrome bd Oxidase

“…Therefore, the SAR data for side-chain variations indicates that farnesyl is the optimal length for maintaining potent inhibition of Mtb cyt-bd oxidase. Recently, shorter-chain analogues of aurachin D (e.g., a heptyl chain) were shown to be potent inhibitors of Escherichia coli cyt-bd oxidase, 35 observed for the similar-length citronellyl analogue 1d against the Mtb cyt-bd oxidase variant. Attention was next shifted to investigate the SAR at C6 and C7 of the 4(1H)-quinolone.…”

Recent Advances in Structural Studies of Cytochrome bd and Its Potential Application as a Drug Target

“…Radloff et al studied the inhibitory effects of aurachin C and new aurachin D derivatives on the ubiquinol-1:O 2 oxidoreductase activity of the isolated cytochromes bd -I, bd -II, and bo 3 from E. coli (strains C43 Δ bo 3 /pET17b- cydABX -StrepII, C43 Δ bo 3 /pET17b- appCBX -StrepII, and GO195 pIRHisA, respectively) [ 118 ]. Long- (C10, decyl or longer) and short-chain (C4, butyl to C8, octyl) aurachin D derivatives were synthesized.…”

“…Among the inhibitors tested, AD7-1 combines properties of high inhibitory potency and selectivity for cytochrome bd -I while causing no inhibition of cytochrome bo 3 in the low nanomolar to micromolar range. It was concluded that AD7-1 could be the promising candidate for trials on a physiological level [ 118 ].…”

“…See the main text for details. Data collected from: [ 10 , 13 , 14 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 ].…”

Bioenergetics and Reactive Nitrogen Species in Bacteria

“…They contribute significantly to the ability of bacteria to resist stresses induced by peroxide [49,[112][113][114][115][116], sulfide [5,[117][118][119][120], ammonia [121], chromate [122], cyanide [117,123]. Due to the fact that the bd oxidases are often found in pathogenic bacteria but absent in humans, they can be used as protein targets for next-generation antimicrobials [43,64,68,[124][125][126][127][128][129][130][131][132][133][134].…”