Relationship of Cytotoxic and Antimicrobial Effects of Triphenylphosphonium Conjugates with Various Quinone Derivatives

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Pavel A. Nazarov^1,a*, Lyudmila A. Zinovkina², Anna A. Brezgunova^1,2, Konstantin G. Lyamzaev^1,3, Andrei V. Golovin^1,2, Marina V. Karakozova¹, Elena A. Kotova¹, Egor Yu. Plotnikov¹, Roman A. Zinovkin^1,3, Maxim V. Skulachev^1,4, and Yuri N. Antonenko¹

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

²Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia

³Russian Clinical Research Center for Gerontology of the Ministry of Healthcare of the Russian Federation, Pirogov Russian National Research Medical University, 129226 Moscow, Russia

⁴Institute of Mitoengineering, Lomonosov Moscow State University, 119991 Moscow, Russia

Received December 4, 2023; Revised January 30, 2024; Accepted February 21, 2024

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Quinone derivatives of triphenylphosphonium have proven themselves to be effective geroprotectors and antioxidants that prevent oxidation of cell components with participation of active free radicals – peroxide (RO₂·), alkoxy (RO·), and alkyl (R·) radicals, as well as reactive oxygen species (superoxide anion, singlet oxygen). Their most studied representatives are derivatives of plastoquinone (SkQ1) and ubiquinone (MitoQ), which in addition to antioxidant properties also have a strong antibacterial effect. In this study, we investigated antibacterial properties of other quinone derivatives based on decyltriphenylphosphonium (SkQ3, SkQT, and SkQThy). We have shown that they, just like SkQ1, inhibit growth of various Gram-positive bacteria at micromolar concentrations, while being less effective against Gram-negative bacteria, which is associated with recognition of the triphenylphosphonium derivatives by the main multidrug resistance (MDR) pump of Gram-negative bacteria, AcrAB-TolC. Antibacterial action of SkQ1 itself was found to be dependent on the number of bacterial cells. It is important to note that the cytotoxic effect of SkQ1 on mammalian cells was observed at higher concentrations than the antibacterial action, which can be explained by (i) the presence of a large number of membrane organelles, (ii) lower membrane potential, (iii) spatial separation of the processes of energy generation and transport, and (iv) differences in the composition of MDR pumps. Differences in the cytotoxic effects on different types of eukaryotic cells may be associated with the degree of membrane organelle development, energy status of the cell, and level of the MDR pump expression.

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KEY WORDS: antioxidants, SkQ1, MDR pumps, AcrAB-TolC, bacteria, mammalian cell cultures, cytotoxicity, antibiotic, mitochondria

DOI: 10.1134/S0006297924020032

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