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Article

Development of Naphthalene-Derivative Bis-QACs as Potent Antimicrobials: Unraveling Structure–Activity Relationship and Microbiological Properties

by
Nikita A. Frolov
1,
Mary A. Seferyan
1,
Elena V. Detusheva
2,
Elizabeth Son
2,
Ilya G. Kolmakov
1,3,
Alena S. Kartseva
2,
Victoria V. Firstova
2,
Anatoly N. Vereshchagin
1,* and
Michail N. Elinson
1,*
1
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, 119991 Moscow, Russia
2
State Research Center for Applied Microbiology and Biotechnology, Obolensk, 142279 Serpukhov, Russia
3
Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1-3, 119991 Moscow, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(23), 5526; https://doi.org/10.3390/molecules29235526
Submission received: 2 October 2024 / Revised: 8 November 2024 / Accepted: 18 November 2024 / Published: 22 November 2024
Versions Notes

Abstract

While the pandemic is behind us, the world community faces a global threat of bacterial resistance outbreak. One of the key ways to combat the spread of multi-resistant bacteria is infection prevention and control tactics using modern antiseptic and disinfectant compositions. Herein, we continue the path to unravel the structure–activity relationship (SAR) of potent pyridine-derived biocide class bis-quaternary ammonium compounds (QACs). In this study, twenty dihydroxynaphthalene-derivative bis-QACs were subjected to extensive microbiological analysis on planktonic cells and biofilms of the ESKAPE microorganisms. Among them, hit compounds were superior in their bacteriostatic and bactericidal action to commercial mono-QACs and were comparable to the best bis-QAC antiseptic on the market. SAR analysis indicated that the linker conformation does not significantly affect the activity, though structure symmetry and especially lipophilicity had an influence on antibacterial performance. Furthermore, we delve deeper in investigation of the antimicrobial potential of bis-QACs and conducted a variety of assays, including time–kill kinetics, bacterial resistance formation, cell morphology, and cytotoxicity. Studies showed promising results for compounds 5d and 6d, indicating 2 to 3-fold less cytotoxicity and hemotoxicity compared to commercial QACs. Moreover, SEM imaging revealed that bis-QACs can cause severe membrane damage to S. aureus and P. aeruginosa strains, confirming great potential of novel compounds as antiseptic and disinfectant.
Keywords: quaternary ammonium compounds; antibacterials; antibiofilm agents; SAR; antiseptics; disinfectant; multi-resistant bacteria; ESKAPE quaternary ammonium compounds; antibacterials; antibiofilm agents; SAR; antiseptics; disinfectant; multi-resistant bacteria; ESKAPE

Share and Cite

MDPI and ACS Style

Frolov, N.A.; Seferyan, M.A.; Detusheva, E.V.; Son, E.; Kolmakov, I.G.; Kartseva, A.S.; Firstova, V.V.; Vereshchagin, A.N.; Elinson, M.N. Development of Naphthalene-Derivative Bis-QACs as Potent Antimicrobials: Unraveling Structure–Activity Relationship and Microbiological Properties. Molecules 2024, 29, 5526. https://doi.org/10.3390/molecules29235526

AMA Style

Frolov NA, Seferyan MA, Detusheva EV, Son E, Kolmakov IG, Kartseva AS, Firstova VV, Vereshchagin AN, Elinson MN. Development of Naphthalene-Derivative Bis-QACs as Potent Antimicrobials: Unraveling Structure–Activity Relationship and Microbiological Properties. Molecules. 2024; 29(23):5526. https://doi.org/10.3390/molecules29235526

Chicago/Turabian Style

Frolov, Nikita A., Mary A. Seferyan, Elena V. Detusheva, Elizabeth Son, Ilya G. Kolmakov, Alena S. Kartseva, Victoria V. Firstova, Anatoly N. Vereshchagin, and Michail N. Elinson. 2024. "Development of Naphthalene-Derivative Bis-QACs as Potent Antimicrobials: Unraveling Structure–Activity Relationship and Microbiological Properties" Molecules 29, no. 23: 5526. https://doi.org/10.3390/molecules29235526

APA Style

Frolov, N. A., Seferyan, M. A., Detusheva, E. V., Son, E., Kolmakov, I. G., Kartseva, A. S., Firstova, V. V., Vereshchagin, A. N., & Elinson, M. N. (2024). Development of Naphthalene-Derivative Bis-QACs as Potent Antimicrobials: Unraveling Structure–Activity Relationship and Microbiological Properties. Molecules, 29(23), 5526. https://doi.org/10.3390/molecules29235526

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