vestibИзвестия Национальной академии наук Беларуси. Серия биологических наукProceedings of the National Academy of Sciences of Belarus, Biological Series1029-89402524-230XThe Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1029-8940-2023-68-1-55-63vestib-850Research ArticleСтатьиОценка влияния модифицированных пиримидиновых производных нуклеиновых кислот на бактериальные клеткиEstimation of the activity of modified pyrimidine nucleoside derivatives on bacteria cellsШихадА.ShihadA.

Аршед Шихад – аспирант

ул. Долгобродская, 23/1, 220070, г. Минск

Arshed Shihad – Postgraduate student

23/1, Dolgobrodskaya Str., 220070, Minsk

almansoriarshed@gmail.comСысаА. Г.SysaA. G.

Алексей Григорьевич Сыса – канд. хим. наук, доцент

ул. Долгобродская, 23/1, 220070, г. Минск

Aliaksei G. Sysa – Ph. D. (Chem.), Associate Professor

23/1, Dolgobrodskaya Str., 220070, Minsk

aliaksei.sysa@iseu.byМеждународный государственный экологический институт имени А. Д. Сахарова Белорусского государственного университетаInternational Sakharov Environmental Institute of Belarusian State University2023100220236815563Copyright © Шихад А., Сыса А.Г., 20232023Шихад А., Сыса А.Г.Shihad A., Sysa A.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestibio.belnauka.by/jour/article/view/850

Широкое применение антибиотиков привело к возникновению и быстрому распространению резистентности у микроорганизмов, что обусловливает необходимость поиска новых классов антибактериальных препаратов. Хорошо известна способность производных компонентов нуклеиновых кислот ингибировать рост эукариотических клеток, однако их антимикробные свойства изучены недостаточно. Нами обнаружено, что модифицированные нуклеозиды арабинофуранозилцитозин (цитарабин, ara-C), [1-(2′,3′,5′-три-О-ацетил-β-D-рибофуранозил)- 4-(1,2,4-триазол-1-ил)]урацил (TTU) и нуклеотиды цитарабин-5′-монофосфат (ara-CMP) и O2,2′-циклоцитидин- 5′-монофосфат (циклоцитидинмонофосфат, цикло-CMP) способны ингибировать рост штаммов Escherichia coli, Sarcina lutea, Bacillus cereus и Proteus mirabilis. Показано, что грамотрицательные бактериальные штаммы (E. coli и P. mirabilis) более чувствительны к воздействию TTU и цикло-CMP и менее чувствительны к воздействию ara-C и ara-CMP по сравнению с грамположительными. Наиболее эффективным ингибитором роста клеток грамположи- тельных штаммов (S. lutea, B. cereus) оказался ара-CMP с ED50 = 5,2–10–5 и ED50 = 3,1·10–4 М соответственно. S. lutea оказалась наиболее чувствительным штаммом бактерий к воздействию всех изученных соединений. Установлено, что изученные модифицированные производные пиримидиновых нуклеозидов усиливают выработку внутриклеточных активных форм кислорода (АФК). Наибольшее повышение уровня АФК при культивировании клеток обнаружено в случае грамотрицательного штамма E. coli в присутствии TTU, а также цикло-CMP, что сильно коррелирует с эффектом ингибирования роста клеток. Обнаружена сильная корреляция между уровнем АФК и жизнеспособностью штамма B. cereus после культивирования с ara-CMP.

The increase in prevalence of antimicrobial-resistant bacteria (ARB) is currently a serious threat, thus there is a need for new classes antimicrobial compounds to combat infections caused by these ARB. The growth inhibition ability of derivatives of the components of nucleic acids has been well-characterized but not for its antimicrobial characteristics. It was found that modified nucleosides arabinofuranosylcytosine (cytarabine, ara-C), [1-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)- 4-(1,2,4-triazol-1-yl)]uracil (TTU), and nucleotides cytarabine-5′-monophosphate (ara-CMP), and O2,2′-cyclocytidine-5′- monophosphate (cyclocytidine monophosphate, cyclo-CMP) were able to inhibit Escherichia coli, Sarcina lutea, Bacillus cereus, and Proteus mirabilis strains in a time and dose dependent manner via killing kinetics assay. It was demonstrated that studied modified pyrimidine nucleosides derivatives enhanced the production of intracellular reactive oxygen species (ROS) over time (validated via DCFA-DA probe assay). This study has revealed the mechanism of action of cytarabine, cyclocytidine monophosphate, and TTU as an antimicrobial agent for the first time, and has shown that these pyrimidine derivatives enhanced might be able to combat infections caused by E. coli, S. lutea, B. cereus, and P. mirabilis in the future.

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The authors declare that there are no conflicts of interest present.