Identification and optimization of quinolone-based inhibitors against cytochrome bd oxidase using an electrochemical assay

Makarchuk, Iryna; Nikolaev, Anton; Thesseling, Alexander; Dejon, Lisa; Lamberty, Daniel; Stief, Laura; Speicher, Andreas; Friedrich, Thorsten; Hellwig, Petra; Nasiri, Hamid R.; Melin, Frédéric

doi:10.1016/j.electacta.2021.138293

Cited by 9 publications

(8 citation statements)

References 55 publications

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“…Makarchuk et al screened a target-focused library of small molecules that contains a set of quinones, naphthoquinones, phenols, quinolones, coumarins, and flavonoids to identify potential inhibitors of cytochrome bd -I from E. coli (strain BL21 Δ cyo /pET28a cydA h BX ) using protein film voltammetry [ 120 ]. As such, quinolones with alkyl or iodine substituents in positions C-2 and C-3 were identified.…”

Section: Cytochrome Bd As a Prospective Target For...mentioning

confidence: 99%

“…The most active inhibitors were produced by chemical modification of the quinolone core and the introduction of an isoprenyl chain in position C-3. The authors showed that the inhibitory efficiency of these compounds increases from one to two isoprene repetitive units and decreases for longer chains [ 120 ].…”

Section: Cytochrome Bd As a Prospective Target For...mentioning

confidence: 99%

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

Section: Figurementioning

confidence: 99%

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

Friedrich

Wohlwend

Borisov

2022

IJMS

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Cytochrome bd is a triheme copper-free terminal oxidase in membrane respiratory chains of prokaryotes. This unique molecular machine couples electron transfer from quinol to O2 with the generation of a proton motive force without proton pumping. Apart from energy conservation, the bd enzyme plays an additional key role in the microbial cell, being involved in the response to different environmental stressors. Cytochrome bd promotes virulence in a number of pathogenic species that makes it a suitable molecular drug target candidate. This review focuses on recent advances in understanding the structure of cytochrome bd and the development of its selective inhibitors.

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Section: Cytochrome Bd As a Prospective Target For...mentioning

confidence: 99%

Section: Cytochrome Bd As a Prospective Target For...mentioning

confidence: 99%

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

Friedrich

Wohlwend

Borisov

2022

IJMS

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“…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].…”

Section: Bacterial Aerobic Respiratory Chainsmentioning

confidence: 99%

Bioenergetics and Reactive Nitrogen Species in Bacteria

Borisov

Forte

2022

IJMS

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The production of reactive nitrogen species (RNS) by the innate immune system is part of the host's defense against invading pathogenic bacteria. In this review, we summarize recent studies on the molecular basis of the effects of nitric oxide and peroxynitrite on microbial respiration and energy conservation. We discuss possible molecular mechanisms underlying RNS resistance in bacteria mediated by unique respiratory oxygen reductases, the mycobacterial bcc-aa3 supercomplex, and bd-type cytochromes. A complete picture of the impact of RNS on microbial bioenergetics is not yet available. However, this research area is developing very rapidly, and the knowledge gained should help us develop new methods of treating infectious diseases.

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“…Menaquinol and demethylmenaquinol are found to be mainly present under microaerobic or anaerobic conditions 15 , 16 . Consequently, aurachins have been used in functional and structural studies of bd -type oxidases, due to their selectivity and good activity 17 , 18 . Interaction studies of decyl-aurachin D with cytochrome bd from Azotobacter vinelandii revealed that decyl-aurachin D acts in the vicinity of heme b -558 and prevents the oxidation of substrate quinols and the resulting electron transfer to heme b-558 .…”

Section: Introductionmentioning

confidence: 99%

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

Radloff

Elamri

Grund

et al. 2021

Sci Rep

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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.

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Identification and optimization of quinolone-based inhibitors against cytochrome bd oxidase using an electrochemical assay

Cited by 9 publications

References 55 publications

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

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

Bioenergetics and Reactive Nitrogen Species in Bacteria

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

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