Derivatives of 4-(1-adamantyl)-phenol are a promising class of antimicrobials affecting the structural integrity and functions of the bacterial cell membrane. The functioning of Pseudomonas aeruginosa respiratory chain and related system of oxidative phosphorylation was investigated before and after treatment with a derivative of 4-(1-adamantyl)-phenol (compound KVM-97). Oxygen consumption was measured polarographically with a Clark-type oxygen electrode. KVM-97 was tested at 0.5× and 1.0× MIC (minimum inhibitory concentration). Specific substrates of the respiratory chain (either 3.0 mM glutamate with 2.0 mM malonate or 3.0 mM succinate with 5.0 μM rotenone) were used. All reactions were stimulated by addition of ADP (0.2 mmol). It was found that at tested concentrations, KVM-97 inhibited the endogenous respiration and substrate oxidation in P. aeruginosa cells. The inhibiting effect was dose-dependent and more pronounced with succinate oxidation rather than glutamate oxidation. The respiratory control index value (RCI) in compound-treated cells was in average 1.5 times lower compared to the intact cells. The decrease in the RCI was related to changing the oxygen uptake rates in state 3 and state 4, which indicate the uncoupling of respiration and oxidative phosphorylation. The data obtained showed that 4-(1-adamantyl)-phenol derivative inhibits oxygen consumption and has uncoupling effects in P. aeruginosa cells.

Одним из основных возбудителей внутрибольничных инфекций является Pseudomonas aeruginosa, высокая устойчивость которого к современным антимикробным средствам приводит к снижению эффективности антибактериальной химиотерапии и необходимости поиска новых активных соединений. Производные адамантана, проявляющие широкий спектр биологической активности, могут быть рассмотрены как перспективный класс веществ с антимикробным действием. Цель. Установить чувствительность и изменения ультраструктуры P. aeruginosa при действии 4-(1адамантил)-фенокси-3-(N-бензил, N-диметиламино)-2-пропанол хлорида (шифр КВМ-97). Материалы и методы. Определение антимикробной активности исследуемого соединения в отношении бактерий рода Pseudomonas проводили методом серийных разведений в жидкой питательной среде. Для изучения влияния соединения на ультраструктуру клеток их инкубировали в течение 1, 3, 6 и 24 ч в среде, содержащей соединение в концентрациях 0,5 МПК и 2,0 МПК. Полученные образцы анализировали методом трансмиссионной электронной микроскопии после контрастирования уранил ацетатом и цитратом свинца. Результаты. Исследование антисинегнойной активности КВМ-97 показало, что соединение ингибирует рост Pseudomonas spp. в концентрации 2,5 мкг/мл. Электронно-микроскопическое исследование показало, что в присутствии КВМ-97 в клетках P. aeruginosa регистрируется повреждение клеточной оболочки и цитоплазматической мембраны (инвагинации, разрывы) с последующей дезорганизацией клеточного содержимого, лизисом и гибелью клеток. Указанные изменения имеют дозозависимый характер, регистрируются уже через 1 час экспозиции с соединением и усиливаются со временем инкубации. Выводы. Проведенные исследования показали, что соединение КВМ-97 проявляет выраженную ингибирующую активность в отношении исследованных бактериальных штаммов. Обнаруженные изменения ультраструктуры P. aeruginosa свидетельствуют, что одним из механизмов действия 4-(1адамантил)-фенокси-3-(N-бензил, N-диметиламино)-2-пропанол хлорида является влияние на мембранный аппарат бактериальной клетки. Ключевые слова: производные адамантана, механизм действия, ультраструктура клетки, Pseudomonas aeruginosa, антибактериальное действие. Дата надходження рукопису 17.05.2018 Дудикова Дарья Маратовна, младший научный сотрудник, Лаборатория фармакологии противомикробных средств, Институт фармакологии и токсикологии Национальной академии медицинских наук Украины, ул. Антона Цедика,

Synthesis and biological activity of novel adamantane-based dialkylaminopropanol quaternary salts Topicality. The emergence and spread of multidrug-resistant pathogens leads to a decrease in efficacy of antibiotic therapy, causes the duration of patient's hospital stay and increases treatment costs. The screening of potential antimicrobial agents among the new classes of chemical compounds is one of the promising methods to overcome the problem of resistance. Aim. To synthesize and to make screening studies of antimicrobial activity of quaternary salts of adamantane derivatives (3a-3l) with the aim to find of new prospective compound with good activity. Materials and methods. The synthesis and investigation of physicochemical properties of new adamantane-based dialkylaminopropanol quaternary salts were carried out. The evaluation of antimicrobial action against S. aureus, E. coli and C. albicans strains were performed. Results and discussion. The results showed that the inhibitory activities of quaternary salts with 1-adamantylethyl radical in their alkoxy group were significantly higher than those of the compounds with 1-adamantyl and 1-adamantyloxyethyl radicals in their alkoxy group. Conclusions. 3c was the most active compound tested against all strains, with MIC between 1.56 and 3.12 µg/mL, and its antimicrobial activity was similar to that of myramistin.

Bacterial biofilm, particularly formed by Pseudomonas aeruginosa, are a cause of severe chronic infectious diseases. Bacteria within a biofilm are phenotypically more resistant to antibiotics and the macroorganism immune system, making it an important virulence factor for many microbes. The aminopropanol derivatives with adamantyl (KVM-97) and N-alkylaryl radicals (KVM-194, KVM-204, KVM-261, and KVM-262) were used as study object. The aim of this study was to investigate the antibiofilm activity of compounds on biofilm formation and on mature biofilm of P. aeruginosa. The effects of the aminopropanol derivatives on the biofilm mass were evaluated by using crystal violet assay. Ciprofloxacin, meropenem, ceftazidime, gentamicin were used as reference substances. Reported results demonstrate that all compounds displayed antibiofilm activity at the tested concentrations. Remarkable reduction in biofilm formation of P. aeruginosa was found after treatment with KVM-97, KVM-261 and KVM-262 in high concentration (5× MIC), biofilm inhibition activity were 84.3%, 90.5% and 83.3% respectively. After a treatment with KVM-204 at 250 μg/ml (5× MIC) 76.6% of the preformed 24-hr biofilms were destroyed. Furthermore, compounds KVM-97, KVM-194, and KVM-261 in both concentrations showed potent antibiofilm activity against the P. aeruginosa, inhibition activity values being between 56.7 and 65.7%. All tested compounds in dose-dependent manner exhibited pronounced inhibition activity against mature 5-days P. аeruginosa biofilm. It was also observed that tested compounds show high antibiofilm activity in comparison to reference antimicrobials. The aminopropanol derivatives may provide templates for a new group of antimicrobial agents and potential future therapeutics for treating chronic infections.

Development of microbial resistance to current antimicrobial drugs created a critical need of the new antiseptics. The object of our study was phenyladamantane derivative (4-(adamantyl-1)-1-(1-aminobutyl)benzol, AM-166). The aim of the presented study was to investigate the specific activity of 4% AM-166 solution in isopropanol and 5% AM-166 solution in 76% ethanol (manufactured by PJSC SIC «Borshchahivskiy CPP») against the wide spectrum of bacteria and fungi, and effective concentrations and exposition time determination. Desinfectant/antiseptic activity was evaluated by quantitative suspension method with subsequent neutralization. Our results showed that both solutions exhibited similar activity against gram-positive and gram-negative bacteria as well as against yeasts. Antibacterial and antifungal action was demonstrated for all investigated concentrations (initial solution, 5-fold and 10-fold dilutions), observed effect was maintained throughout the whole observation period (from 5 to 30 min). Tested solutions in initial concentrations demonstrated fungicidal activity against A. niger. 5-fold dilution of 5% AM-166 solution in 76% ethanol was more effective than 5-fold dilution of 4% AM-166 solution in isopropanol. 10-fold dilutions of both solutions were ineffective against A. niger. The data obtained suggest the prospects of adamantane derivatives for the development of novel antiseptics.