Synthesis and Antimicrobial Activities of Phosphonium Salts on Basis of Triphenylphosphine and 3,5-Di-Tert-Butyl-4-Hydroxybenzyl Bromide

Галкина, И. В.; Bakhtiyarova, Yu. V.; Andriyashin, V. V.; Галкин, В. И.; Черкасов, Р. А.

doi:10.1080/10426507.2012.740694

Cited by 17 publications

(4 citation statements)

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“…The antibacterial action of SkQ1 and MitoQ is obviously related to the antimicrobial activity of alkyl trimethyl 3 , alkyl trihexyl 5 and alkyl triphenyl 7 , 8 phosphonium salts, which was attributed, in particular, to membrane-perturbing effects of QPC 6 , 9 , similar to QAC 4 , 57 – 59 . Of note, as a pro- or antioxidant, SkQ1 might be involved in ROS-production/suppression.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-targeted antioxidants as highly effective antibiotics

Nazarov

Osterman

Tokarchuk

et al. 2017

Sci Rep

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Mitochondria-targeted antioxidants are known to alleviate mitochondrial oxidative damage that is associated with a variety of diseases. Here, we showed that SkQ1, a decyltriphenyl phosphonium cation conjugated to a quinone moiety, exhibited strong antibacterial activity towards Gram-positive Bacillus subtilis, Mycobacterium sp. and Staphylococcus aureus and Gram-negative Photobacterium phosphoreum and Rhodobacter sphaeroides in submicromolar and micromolar concentrations. SkQ1 exhibited less antibiotic activity towards Escherichia coli due to the presence of the highly effective multidrug resistance pump AcrAB-TolC. E. coli mutants lacking AcrAB-TolC showed similar SkQ1 sensitivity, as B. subtilis. Lowering of the bacterial membrane potential by SkQ1 might be involved in the mechanism of its bactericidal action. No significant cytotoxic effect on mammalian cells was observed at bacteriotoxic concentrations of SkQ1. Therefore, SkQ1 may be effective in protection of the infected mammals by killing invading bacteria.

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Section: Discussionmentioning

confidence: 99%

Mitochondria-targeted antioxidants as highly effective antibiotics

Nazarov

Osterman

Tokarchuk

et al. 2017

Sci Rep

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“…Despite a long history of their practical use and laboratory studies, an exact mechanism of their action has not been fully understood. In particular, speculations on the mechanistic role of their membrane activity ranged from an unspecific effect on permeability of biological membranes and damaging bacterial cell wall , to proton-shuttling activity via catalysis of fatty-acid transfer . Since mitochondrial uncoupling by using low doses of protonophores is known to be beneficial for cells undergoing oxidative stress, several attempts have been made to synthesize mitochondria-targeted protonophores via conjugation of a triphenylphosphonium (TPP) cation to various protonophores such as 2,4-dinitrophenol (DNP), bis- tert -butylphenol, quercetin, and fluorescein. , The majority of mitochondrial uncouplers, capable of dissipating proton gradient generated by respiratory proton pumps on the inner mitochondrial membrane, represent aromatic weak acids that can penetrate through membranes both in deprotonated anionic and protonated neutral forms .…”

Section: Introductionmentioning

confidence: 99%

Zwitterionic Protonophore Derived from 2-(2-Hydroxyaryl)alkenylphosphonium as an Uncoupler of Oxidative Phosphorylation

et al. 2019

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2-(2-Hydroxyaryl)alkenylphosphonium salts (here coined as PPR) representing derivatives of quaternary phosphonium with two phenyl (P) and one alkyl (R) substituents linked through alkenyl bridge to substituted phenol were applied here to planar bilayer lipid membranes (BLM), isolated mitochondria, and cell culture. PPR with six carbon atoms in R (PP6) induced proton-selective currents across BLM and caused mitochondrial uncoupling. In particular, PP6 at submicromolar concentrations accelerated respiration, decreased membrane potential, and reduced ATP synthesis in isolated rat liver mitochondria (RLM). Methylation of a hydroxyl group substantially suppressed the protonophoric activity of PP6 on BLM and its uncoupling potency in RLM. Of note, the methylated derivative PP6-OMe was synthesized here via a new synthetic route including cyclization of PP6 with subsequent ring opening. PPR were considered as protonophoric uncouplers of a zwitterionic type, capable of penetrating membranes both as a zwitterion composed of a deprotonated phenol and a cationic quaternary phosphonium, and as a protonated cation. The protonophoric and uncoupling properties of PPR found here were speculated to account for their strong antibacterial activity described previously.

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“…Четвертичные производные аммония и фосфония исполь-зуются в качестве антисептиков и дезинфектантов уже не одно десятилетие [23][24][25][26][27][28]. Недавно были разработаны вещества, имеющие в своем составе антиоксидантную группу и компонент, воздействующий на митохондрии.…”

Section: соединения на основе трифенилфосфонияunclassified

Производные Трифенилфосфония Как Альтернатива Обычным Антибиотикам

Пинто¹,

Банержи²,

Nazarov³

2018

Вестник РГМУ

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There is an urgent need for new antimicrobial and therapeutic strategies to deal with the ever evolving antimicrobial resistance among the most prevalent bacterial pathogens. Infections due to virulent bacteria remain significant causes of morbidity and mortality despite progress in antimicrobial therapy, primarily because of the increasing of antimicrobial resistance levels among such group of bacteria. Despite significant advances in the understanding of the pathogenesis of infection due to these organisms, there are only limited strategies to prevent infection. Recently it was reported that SkQ1, triphenyl phosphoniumbased mitochondria-targeted antioxidant and antibiotic, effectively kills all tested Gram-positive laboratory strains including of Bacillus subtilis, Staphylococcus aureus and Mycobacterium sp. Moreover, SkQ1 demonstrated effectiveness towards Gram-negative strains too, except Escherichia coli. The mechanism of the bactericidal action of TPP-based antibiotics could be also described by its ability to suppress bacterial bioenergetics by collapsing membrane potential through activation of protonophorous uncoupling. To this date, there are no reports of resistance to SkQ1 among Gram-positive strains; therefore, triphenyl phosphonium-based antibacterial agents would be effective towards planktonic and sessile cells of clinical resistant strains.В связи с тем, что наиболее распространенные патогены постоянно эволюционируют, приобретая устойчивость ко все большему числу антибиотиков, в настоящее время существует острая потребность в новых антимикробных препара-тах и стратегиях лечения инфекций, вызываемых антибиотикорезистентными бактериями. Хотя в понимании патогене-за подобных инфекций удалось значительно продвинуться, стратегий для борьбы с ними не так много. Недавно было показано, что SkQ1, антиоксидант и антибиотик на основе трифенилфосфония, воздействующий на митохондрии, эффективен в отношении грамположительных лабораторных штаммов, включая Bacillus subtilis, Staphylococcus aureus и Mycobacterium sp. Более того, SkQ1 также показал эффективность в отношении грамотрицательных штаммов за исключением Escherichia coli. Механизм бактерицидного действия трифенилфосфониевых соединений можно объяс-нить их способностью вызывать нарушения энергетического обмена у бактерий за счет резкого снижения мембранно-го потенциала путем стимуляции протонофорного разобщения. На текущий момент случаи устойчивости к SkQ1 среди грамположительных бактерий не зафиксированы, поэтому антимикробные препараты на основе трифенилфосфония могут быть эффективно использованы для борьбы с планктонными и сессильными клиническими штаммами, не-чувствительными к обычным антибиотикам. Благодарности: авторы благодарят доктора биологических наук Ю. Н. Антоненко и кандидата биологических наук М. В. Скулачева за ценные крити-ческие замечания и обсуждение этой работы.Acknowledgement: we are grateful to Dr. Y. N. Antonenko and Dr. M. V. Skulachev for critical reading and helpful discussion of the manuscript.

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Synthesis and Antimicrobial Activities of Phosphonium Salts on Basis of Triphenylphosphine and 3,5-Di-Tert-Butyl-4-Hydroxybenzyl Bromide

Cited by 17 publications

References 1 publication

Mitochondria-targeted antioxidants as highly effective antibiotics

Mitochondria-targeted antioxidants as highly effective antibiotics

Zwitterionic Protonophore Derived from 2-(2-Hydroxyaryl)alkenylphosphonium as an Uncoupler of Oxidative Phosphorylation

Производные Трифенилфосфония Как Альтернатива Обычным Антибиотикам

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