vestnik-bio-msuВестник Московского университета. Серия 16. БиологияVestnik Moskovskogo universiteta. Seriya 16. Biologiya0137-0952Lomonosov Moscow State University, School of Biology10.55959/MSU0137-0952-16-2022-77-4-215-223vestnik-bio-msu-1182Research ArticleОбзорыПомпы множественной лекарственной устойчивости как краеугольный камень резистентности бактерийMultidrug resistance pumps as a keystone of bacterial resistancehttps://orcid.org/0000-0003-1857-323XНазаровП. А.NazarovP. A.

Назаров Павел Александрович – канд. биол. наук, ст. науч. сотр.

Department of Bioenergetics

1–43 Leninskie gory, Moscow, 119991

nazarovpa@gmail.comhttps://orcid.org/0000-0002-0450-5183КузнецоваА. М.KuznetsovaA. M.

Кузнецова Анна Михайловна – студентка кафедры микробиологии биологического факультета

Department of Microbiology, School of Biology

1–12 Leninskie gory, Moscow, 119234

https://orcid.org/0000-0001-9404-6314КаракозоваМ. В.KarakozovaM. V.

Каракозова Марина Викторовна – канд. биол. наук, науч. сотр.

Center of Life Sciences

30–1 Bolshoy Boulevard, 121205, Moscow

Научно-исследовательский институт физико-химической биологии имени А.Н. Белозерского, Московский государственный университет имени М.В. ЛомоносоваРоссияBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State UniversityRussian FederationLomonosov Moscow State UniversityRussian FederationСколковский институт науки и технологийРоссияSkolkovo Institute of Science and TechnologyRussian Federation202229112022774215223Copyright © Назаров П.А., Кузнецова А.М., Каракозова М.В., 20222022Назаров П.А., Кузнецова А.М., Каракозова М.В.Nazarov P.A., Kuznetsova A.M., Karakozova M.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestnik-bio-msu.elpub.ru/jour/article/view/1182

Устойчивость к антибиотикам представляет собой глобальную проблему современной медицины. Предвестником наступления постантибиотической эры является сложность и дороговизна разработки новых антибиотиков, а также их неэффективность из-за быстро развивающейся устойчивости бактерий. Краеугольным камнем бактериальной защиты от антибиотиков являются помпы множественной лекарственной устойчивости (МЛУ), которые участвуют в формировании устойчивости к ксенобиотикам, экспорте токсинов, поддержании клеточного гомеостаза, образовании биопленок и персистентных клеток. Помпы МЛУ – это основа неспецифической защиты бактерий, в то время как модификация мишени лекарственного средства, инактивация лекарственного средства, переключение мишени или секвестрация мишени – вторая, специфическая, линия их защиты. Таким образом, сформированная помпами МЛУ неспецифическая защита бактерий – барьер, препятствующий попаданию антибактериальных веществ внутрь клетки, что является основным фактором, определяющим устойчивость бактерий. Понимание механизмов работы помп МЛУ и взвешенная оценка их вклада в общую устойчивость, а также в чувствительность к антибиотикам позволят либо серьезно отсрочить наступление постантибиотической эры, либо предотвратить ее наступление в обозримом будущем.

Antibiotic resistance is a global problem of modern medicine. A harbinger of the onset of the post-antibiotic era is the complexity and high cost of developing new antibiotics, as well as their inefficiency due to the rapidly developing resistance of bacteria. The cornerstone of bacterial protection against antibiotics are multidrug resistance pumps (MDR), which are involved in the formation of resistance to xenobiotics, the export of toxins, the maintenance of cellular homeostasis, the formation of biofilms and persistent cells. MDR pumps are the basis for the nonspecific protection of bacteria, while modification of the drug target, inactivation of the drug, switching of the target or sequestration of the target is the second, specific line of their protection. Thus, the nonspecific protection of bacteria formed by MDR pumps is a barrier that prevents the penetration of antibacterial substances into the cell, which is the main factor determining the resistance of bacteria. Understanding the mechanisms of MDR pumps and a balanced assessment of their contribution to overall resistance, as well as to antibiotic sensitivity, will either seriously delay the onset of the post-antibiotic era, or prevent its onset in the foreseeable future.

множественная лекарственная устойчивость (МЛУ)помпыантибиотикиксенобиотикибиопленкиперсистерыбактериофагиmultidrug resistance (MDR)pumpsantibioticsxenobioticsbiofilmspersistersbacteriophagesReferencesWorld Health Organization. 2015. URL: https://www.who.int/publications/i/item/9789241509763 (дата обращения: 15.06.2022).World Health Organization. 2015. URL: https://www.who.int/publications/i/item/9789241509763 (дата обращения: 15.06.2022).World Health Organization. 2014. URL: https://apps.who.int/iris/handle/10665/112642 (дата обращения: 15.06.2022).World Health Organization. 2014. URL: https://apps.who.int/iris/handle/10665/112642 (дата обращения: 15.06.2022).Arason V.A., Gunnlaugsson A., Sigurdsson J.A., Erlendsdottir H., Gudmundsson S., Kristinsson K.G. Clonal spread of resistant pneumococci despite diminished antimicrobial use // Microb. Drug Resist. 2002. Vol. 8. N 3. P. 187–192.Arason V.A., Gunnlaugsson A., Sigurdsson J.A., Erlendsdottir H., Gudmundsson S., Kristinsson K.G. Clonal spread of resistant pneumococci despite diminished antimicrobial use // Microb. Drug Resist. 2002. Vol. 8. N 3. P. 187–192.Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis // Lancet. 2022. Vol. 399 N 10325. P. 629–655.Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis // Lancet. 2022. Vol. 399 N 10325. P. 629–655.Turner B. Tackling antimicrobial resistance and climate change // Lancet. 2018. Vol. 299. N 10163. P. 2435–2436.Turner B. Tackling antimicrobial resistance and climate change // Lancet. 2018. Vol. 299. N 10163. P. 2435–2436.Cooper M.A., Shlaes D. Fix the antibiotics pipeline // Nature. 2011. Vol. 472. N 7341. P. 32.Cooper M.A., Shlaes D. Fix the antibiotics pipeline // Nature. 2011. Vol. 472. N 7341. P. 32.Lewis K. The science of antibiotic discovery // Cell. 2020. Vol. 181. N 1. P. 29–45.Lewis K. The science of antibiotic discovery // Cell. 2020. Vol. 181. N 1. P. 29–45.D’Costa V.M., King C.E., Kalan L., Morar M., Sung W.W., Schwarz C., Froese D., Zazula G., Calmels F., Debruyne R., Golding G.B., Poinar H.N., Wright G.D. Antibiotic resistance is ancient // Nature. 2011. Vol. 477. N 7365. P. 457–461.D’Costa V.M., King C.E., Kalan L., Morar M., Sung W.W., Schwarz C., Froese D., Zazula G., Calmels F., Debruyne R., Golding G.B., Poinar H.N., Wright G.D. Antibiotic resistance is ancient // Nature. 2011. Vol. 477. N 7365. P. 457–461.Reygaert W.C. An overview of the antimicrobial resistance mechanisms of bacteria // AIMS Microbiol. 2018. Vol. 4. N 3. P. 482–501.Reygaert W.C. An overview of the antimicrobial resistance mechanisms of bacteria // AIMS Microbiol. 2018. Vol. 4. N 3. P. 482–501.Chaplin D.D. Overview of the immune response // J. Allergy Clin. Immunol. 2010. Vol. 125. N 2. P. 3–23.Chaplin D.D. Overview of the immune response // J. Allergy Clin. Immunol. 2010. Vol. 125. N 2. P. 3–23.Nazarov P.A., Baleev D.N., Ivanova M.I., Sokolova L.M., Karakozova M.V. Infectious plant diseases: Etiology, current status, problems and prospects in plant protection // Acta Naturae. 2020. Vol. 12 N 3. P. 46–59.Nazarov P.A., Baleev D.N., Ivanova M.I., Sokolova L.M., Karakozova M.V. Infectious plant diseases: Etiology, current status, problems and prospects in plant protection // Acta Naturae. 2020. Vol. 12 N 3. P. 46–59.Смирнова О.Г., Кочетов А.В. Клеточная стенка растений и механизмы устойчивости к патогенам // Вавил. журн. ген. селекц. 2016. Т. 6. № 19. С. 715–723.Смирнова О.Г., Кочетов А.В. Клеточная стенка растений и механизмы устойчивости к патогенам // Вавил. журн. ген. селекц. 2016. Т. 6. № 19. С. 715–723.Nikaido H. RND transporters in the living world // Res. Microbiol. 2018. Vol. 169. N 7–8. P. 363–371.Nikaido H. RND transporters in the living world // Res. Microbiol. 2018. Vol. 169. N 7–8. P. 363–371.Pasqua M., Grossi M., Zennaro A., Fanelli G., Micheli G., Barras F., Colonna B., Prosseda G. The varied role of efflux pumps of the MFS family in the interplay of bacteria with animal and plant cells // Microorganisms. 2019. Vol. 7. N 9: 285.Pasqua M., Grossi M., Zennaro A., Fanelli G., Micheli G., Barras F., Colonna B., Prosseda G. The varied role of efflux pumps of the MFS family in the interplay of bacteria with animal and plant cells // Microorganisms. 2019. Vol. 7. N 9: 285.Nazarov P.A. MDR Pumps as crossroads of resistance: Antibiotics and Bacteriophages // Antibiotics. 2022. Vol. 11. N 6: 734.Nazarov P.A. MDR Pumps as crossroads of resistance: Antibiotics and Bacteriophages // Antibiotics. 2022. Vol. 11. N 6: 734.Anisimov V.N., Egorov M.V., Krasilshchikova M.S., et al. Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents // Aging. 2011. Vol. 3. N 11. P. 1110–1119.Anisimov V.N., Egorov M.V., Krasilshchikova M.S., et al. Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents // Aging. 2011. Vol. 3. N 11. P. 1110–1119.Khailova L.S., Nazarov P.A., Sumbatyan N.V., Korshunova G.A., Rokitskaya T.I., Dedukhova V.I., Antonenko Y.N., Skulachev V.P. Uncoupling and toxic action of alkyltriphenylphosphonium cations on mitochondria and the bacterium Bacillus subtilis as a function of alkyl chain length // Biochemistry (Mosc.). 2015. Vol. 80. N 12. P. 1589–1597.Khailova L.S., Nazarov P.A., Sumbatyan N.V., Korshunova G.A., Rokitskaya T.I., Dedukhova V.I., Antonenko Y.N., Skulachev V.P. Uncoupling and toxic action of alkyltriphenylphosphonium cations on mitochondria and the bacterium Bacillus subtilis as a function of alkyl chain length // Biochemistry (Mosc.). 2015. Vol. 80. N 12. P. 1589–1597.Nazarov P.A., Osterman I.A., Tokarchuk A.V., Karakozova M.V., Korshunova G.A., Lyamzaev K.G., Skulachev M.V., Kotova E.A., Skulachev V.P., Antonenko Y.N. Mitochondria-targeted antioxidants as highly effective antibiotics // Sci. Rep. 2017. Vol. 7. N 1: 1394.Nazarov P.A., Osterman I.A., Tokarchuk A.V., Karakozova M.V., Korshunova G.A., Lyamzaev K.G., Skulachev M.V., Kotova E.A., Skulachev V.P., Antonenko Y.N. Mitochondria-targeted antioxidants as highly effective antibiotics // Sci. Rep. 2017. Vol. 7. N 1: 1394.Nazarov P.A., Kotova E.A., Skulachev V.P., Antonenko Y.N. Genetic variability of the AcrAB-TolC multidrug efflux pump underlies SkQ1 resistance in gramnegative bacteria // Acta Naturae. 2019. Vol. 11. N 4. P. 93–98.Nazarov P.A., Kotova E.A., Skulachev V.P., Antonenko Y.N. Genetic variability of the AcrAB-TolC multidrug efflux pump underlies SkQ1 resistance in gramnegative bacteria // Acta Naturae. 2019. Vol. 11. N 4. P. 93–98.Shi X., Chen M., Yu Z., Bell J.M., Wang H., Forrester I., Villarreal H., Jakana J., Du D., Luisi B.F., Ludtke S.J., Wang Z. In situ structure and assembly of the multidrug efflux pump AcrAB-TolC // Nat. Commun. 2019. Vol. 10. N 1: 2635.Shi X., Chen M., Yu Z., Bell J.M., Wang H., Forrester I., Villarreal H., Jakana J., Du D., Luisi B.F., Ludtke S.J., Wang Z. In situ structure and assembly of the multidrug efflux pump AcrAB-TolC // Nat. Commun. 2019. Vol. 10. N 1: 2635.Nazarov P.A., Sorochkina A.I., Karakozova M.V. New functional criterion for evaluation of homologous MDR pumps // Front. Microbiol. 2020. Vol. 11: 592283.Nazarov P.A., Sorochkina A.I., Karakozova M.V. New functional criterion for evaluation of homologous MDR pumps // Front. Microbiol. 2020. Vol. 11: 592283.García-Contreras R., Martínez-Vázquez M., González-Pedrajo B., Castillo-Juárez I. Editorial: Alternatives to combat bacterial infections // Front. Microbiol. 2022. Vol. 13: 909866.García-Contreras R., Martínez-Vázquez M., González-Pedrajo B., Castillo-Juárez I. Editorial: Alternatives to combat bacterial infections // Front. Microbiol. 2022. Vol. 13: 909866.Sulavik M.C., Houseweart C., Cramer C., Jiwani N., Murgolo N., Greene J., DiDomenico B., Shaw K.J., Miller G.H., Hare R., Shimer G. Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes // Antimicrob. Agents Chemother. 2001. Vol. 45. N 4. P. 1126–1136.Sulavik M.C., Houseweart C., Cramer C., Jiwani N., Murgolo N., Greene J., DiDomenico B., Shaw K.J., Miller G.H., Hare R., Shimer G. Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes // Antimicrob. Agents Chemother. 2001. Vol. 45. N 4. P. 1126–1136.Moisenovich M.M., Ol’shevskaya V.A., Rokitskaya T.I., Ramonova A.A., Nikitina R.G., Savchenko A.N., Tatarskiy V.V. Jr., Kaplan M.A., Kalinin V.N., Kotova E.A., Uvarov O.V., Agapov I.I., Antonenko Y.N., Shtil A.A. Novel photosensitizers trigger rapid death of malignant human cells and rodent tumor transplants via lipid photodamage and membrane permeabilization // PloS One. 2010. Vol. 5. N 9: e12717.Moisenovich M.M., Ol’shevskaya V.A., Rokitskaya T.I., Ramonova A.A., Nikitina R.G., Savchenko A.N., Tatarskiy V.V. Jr., Kaplan M.A., Kalinin V.N., Kotova E.A., Uvarov O.V., Agapov I.I., Antonenko Y.N., Shtil A.A. Novel photosensitizers trigger rapid death of malignant human cells and rodent tumor transplants via lipid photodamage and membrane permeabilization // PloS One. 2010. Vol. 5. N 9: e12717.Omarova E.O., Nazarov P.A., Firsov A.M., Strakhovskaya M.G., Arkhipova A.Y., Moisenovich M.M., Agapov I.I., Ol’shevskaya V.A., Zaitsev A.V., Kalinin V.N., Kotova E.A., Antonenko Y.N. Carboranyl-chlorin e6 as a potent antimicrobial photosensitizer // PLoS One. 2015. Vol. 10. N 11: e0141990.Omarova E.O., Nazarov P.A., Firsov A.M., Strakhovskaya M.G., Arkhipova A.Y., Moisenovich M.M., Agapov I.I., Ol’shevskaya V.A., Zaitsev A.V., Kalinin V.N., Kotova E.A., Antonenko Y.N. Carboranyl-chlorin e6 as a potent antimicrobial photosensitizer // PLoS One. 2015. Vol. 10. N 11: e0141990.Du D., Wang-Kan X., Neuberger A., van Veen H.W., Pos K.M., Piddock L.J.V., Luisi B.F. Multidrug efflux pumps: structure, function and regulation // Nat. Rev. Microbiol. 2018. Vol. 16. N 9. P. 523–539.Du D., Wang-Kan X., Neuberger A., van Veen H.W., Pos K.M., Piddock L.J.V., Luisi B.F. Multidrug efflux pumps: structure, function and regulation // Nat. Rev. Microbiol. 2018. Vol. 16. N 9. P. 523–539.Bot C., Prodan C. Quantifying the membrane potential during E. coli growth stages // Biophys. Chem. 2010. Vol. 146. P. 133–137.Bot C., Prodan C. Quantifying the membrane potential during E. coli growth stages // Biophys. Chem. 2010. Vol. 146. P. 133–137.Du D., Wang Z., James N.R., Voss J.E., Klimont E., Ohene-Agyei T., Venter H., Chiu W., Luisi B.F. Structure of the AcrAB-TolC multidrug efflux pump // Nature. 2014. Vol. 509. N 7501. P. 512–515.Du D., Wang Z., James N.R., Voss J.E., Klimont E., Ohene-Agyei T., Venter H., Chiu W., Luisi B.F. Structure of the AcrAB-TolC multidrug efflux pump // Nature. 2014. Vol. 509. N 7501. P. 512–515.Yu E. W., Aires J.R., Nikaido H. AcrB multidrug efflux pump of Escherichia coli: composite substrate-binding cavity of exceptional flexibility generates its extremely wide substrate specificity // J. Bacteriol. 2003. Vol. 185. N 19. P. 5657–5664.Yu E. W., Aires J.R., Nikaido H. AcrB multidrug efflux pump of Escherichia coli: composite substrate-binding cavity of exceptional flexibility generates its extremely wide substrate specificity // J. Bacteriol. 2003. Vol. 185. N 19. P. 5657–5664.Hobbs E.C., Yin X., Paul B.J., Astarita J.L., Storz G. Conserved small protein associates with the multidrug efflux pump AcrB and differentially affects antibiotic resistance // Proc. Natl. Acad. Sci. U.S.A. 2012. Vol. 109. N 41. P. 16696–16701.Hobbs E.C., Yin X., Paul B.J., Astarita J.L., Storz G. Conserved small protein associates with the multidrug efflux pump AcrB and differentially affects antibiotic resistance // Proc. Natl. Acad. Sci. U.S.A. 2012. Vol. 109. N 41. P. 16696–16701.Storz G., Wolf Y.I., Ramamurthi K.S. Small proteins can no longer be ignored // Annu. Rev. Biochem. 2014. Vol. 83. P. 753–777.Storz G., Wolf Y.I., Ramamurthi K.S. Small proteins can no longer be ignored // Annu. Rev. Biochem. 2014. Vol. 83. P. 753–777.Du D., Neuberger A., Orr M.W., Newman C.E., Hsu P.C., Samsudin F., Szewczak-Harris A., Ramos L.M., Debela M., Khalid S., Storz G., Luisi B.F. Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment // Structure. 2020. Vol. 28. N 6. P. 625–634.Du D., Neuberger A., Orr M.W., Newman C.E., Hsu P.C., Samsudin F., Szewczak-Harris A., Ramos L.M., Debela M., Khalid S., Storz G., Luisi B.F. Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment // Structure. 2020. Vol. 28. N 6. P. 625–634.Rosenberg E.Y., Ma D., Nikaido H. AcrD of Escherichia coli is an aminoglycoside efflux pump // J. Bacteriol. 2000. Vol. 182. N 6. P. 1754–1756.Rosenberg E.Y., Ma D., Nikaido H. AcrD of Escherichia coli is an aminoglycoside efflux pump // J. Bacteriol. 2000. Vol. 182. N 6. P. 1754–1756.Pos K.M. Drug transport mechanism of the AcrB efflux pump // Biochim. Biophys. Acta. 2009. Vol. 1794. N 5. P. 782–793.Pos K.M. Drug transport mechanism of the AcrB efflux pump // Biochim. Biophys. Acta. 2009. Vol. 1794. N 5. P. 782–793.Seeger M.A., Schiefner A., Eicher T., Verrey F., Diederichs K., Pos K.M. Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism // Science. 2006. Vol. 313. N 5791. P. 1295–1298.Seeger M.A., Schiefner A., Eicher T., Verrey F., Diederichs K., Pos K.M. Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism // Science. 2006. Vol. 313. N 5791. P. 1295–1298.Nikaido H., Takatsuka Y. Mechanisms of RND multidrug efflux pumps // Biochim. Biophys. Acta 2009. Vol. 1794. N 5. P. 769–781.Nikaido H., Takatsuka Y. Mechanisms of RND multidrug efflux pumps // Biochim. Biophys. Acta 2009. Vol. 1794. N 5. P. 769–781.Eicher T., Cha H.J., Seeger M.A., Brandstätter L., El-Delik J., Bohnert J.A., Kern W.V., Verrey F., Grütter M.G., Diederichs K., Pos K.M. Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop // Proc. Natl. Acad. Sci. U.S.A. 2012. Vol. 109. N 15. P. 5687–5692.Eicher T., Cha H.J., Seeger M.A., Brandstätter L., El-Delik J., Bohnert J.A., Kern W.V., Verrey F., Grütter M.G., Diederichs K., Pos K.M. Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop // Proc. Natl. Acad. Sci. U.S.A. 2012. Vol. 109. N 15. P. 5687–5692.Husain F., Nikaido H. Substrate path in the AcrB multidrug efflux pump of Escherichia coli // Mol. Microbiol. 2010. Vol. 78. N 2. P. 320–330.Husain F., Nikaido H. Substrate path in the AcrB multidrug efflux pump of Escherichia coli // Mol. Microbiol. 2010. Vol. 78. N 2. P. 320–330.Tam H.K., Foong W.E., Oswald C., Herrmann A., Zeng H., Pos K.M. Allosteric drug transport mechanism of multidrug transporter AcrB // Nat. Commun. 2021. Vol. 12. N 1: 3889.Tam H.K., Foong W.E., Oswald C., Herrmann A., Zeng H., Pos K.M. Allosteric drug transport mechanism of multidrug transporter AcrB // Nat. Commun. 2021. Vol. 12. N 1: 3889.Webber A., Ratnaweera M., Harris A., Luisi B.F., Ntsogo Enguéné V.Y. A model for allosteric communication in drug transport by the AcrAB-TolC tripartite efflux pump // Antibiotics. 2022. Vol. 11. N 1: 52.Webber A., Ratnaweera M., Harris A., Luisi B.F., Ntsogo Enguéné V.Y. A model for allosteric communication in drug transport by the AcrAB-TolC tripartite efflux pump // Antibiotics. 2022. Vol. 11. N 1: 52.Sandhu P., Akhter Y. Evolution of structural fitness and multifunctional aspects of mycobacterial RND family transporters // Arch. Microbiol. 2018. Vol. 200. N 1. P. 19–31.Sandhu P., Akhter Y. Evolution of structural fitness and multifunctional aspects of mycobacterial RND family transporters // Arch. Microbiol. 2018. Vol. 200. N 1. P. 19–31.Pasqua M., Bonaccorsi di Patti M.C., Fanelli G., Utsumi R., Eguchi Y., Trirocco R., Prosseda G., Grossi M., Colonna B. Host-bacterial pathogen communication: The wily role of the multidrug efflux pumps of the MFS family // Front. Mol. Biosci. 2021. Vol. 8: 723274.Pasqua M., Bonaccorsi di Patti M.C., Fanelli G., Utsumi R., Eguchi Y., Trirocco R., Prosseda G., Grossi M., Colonna B. Host-bacterial pathogen communication: The wily role of the multidrug efflux pumps of the MFS family // Front. Mol. Biosci. 2021. Vol. 8: 723274.Karakozova M., Nazarov P. Conserved sequences of genes coding for the multidrug resistance pump AcrABTolC of Escherichia coli suggest their involvement into permanent cell “cleaning” // Bull. Russ. State Med. Univ. 2018. N. 2. P. 32–36.Karakozova M., Nazarov P. Conserved sequences of genes coding for the multidrug resistance pump AcrABTolC of Escherichia coli suggest their involvement into permanent cell “cleaning” // Bull. Russ. State Med. Univ. 2018. N. 2. P. 32–36.Tamer Y.T., Gaszek I., Rodrigues M., Coskun F.S., Farid M., Koh A.Y., Russ W., Toprak E. The antibiotic efflux protein TolC is a highly evolvable target under Colicin E1 or TLS phage selection // Mol. Biol. Evol. 2021. Vol. 38. N 10. P. 4493–4504.Tamer Y.T., Gaszek I., Rodrigues M., Coskun F.S., Farid M., Koh A.Y., Russ W., Toprak E. The antibiotic efflux protein TolC is a highly evolvable target under Colicin E1 or TLS phage selection // Mol. Biol. Evol. 2021. Vol. 38. N 10. P. 4493–4504.Esteves N.C., Porwollik S., McClelland M., Scharf B.E. The multidrug efflux system AcrABZ-TolC is essential for infection of Salmonella typhimurium by the flagellum-dependent bacteriophage Chi // J. Virol. 2021. Vol. 95. N 11: e00394-21.Esteves N.C., Porwollik S., McClelland M., Scharf B.E. The multidrug efflux system AcrABZ-TolC is essential for infection of Salmonella typhimurium by the flagellum-dependent bacteriophage Chi // J. Virol. 2021. Vol. 95. N 11: e00394-21.Saier M.H. Jr., Paulsen I.T., Sliwinski M.K., Pao S.S., Skurray R.A., Nikaido H. Evolutionary origins of multidrug and drug-specific efflux pumps in bacteria // FASEB J. 1998. Vol. 12. N 3. P. 265–274.Saier M.H. Jr., Paulsen I.T., Sliwinski M.K., Pao S.S., Skurray R.A., Nikaido H. Evolutionary origins of multidrug and drug-specific efflux pumps in bacteria // FASEB J. 1998. Vol. 12. N 3. P. 265–274.Hansen L.H., Jensen L.B., Sørensen H.I., Sørensen S.J. Substrate specificity of the OqxAB multidrug resistance pump in Escherichia coli and selected enteric bacteria // J. Antimicrob. Chemother. 2007. Vol. 60. N 1. P. 145–147.Hansen L.H., Jensen L.B., Sørensen H.I., Sørensen S.J. Substrate specificity of the OqxAB multidrug resistance pump in Escherichia coli and selected enteric bacteria // J. Antimicrob. Chemother. 2007. Vol. 60. N 1. P. 145–147.Harmer C.J., Hall R.M. An analysis of the IS6/IS26 family of insertion sequences: is it a single family? // Microb. Genom. 2019. Vol. 5. N. 9: e000291.Harmer C.J., Hall R.M. An analysis of the IS6/IS26 family of insertion sequences: is it a single family? // Microb. Genom. 2019. Vol. 5. N. 9: e000291.Li J., Zhang H., Ning J., Sajid A., Cheng G., Yuan Z., Hao H. The nature and epidemiology of OqxAB, a multidrug efflux pump // Antimicrob. Resist. Infect. Control. 2019. Vol. 8: 44.Li J., Zhang H., Ning J., Sajid A., Cheng G., Yuan Z., Hao H. The nature and epidemiology of OqxAB, a multidrug efflux pump // Antimicrob. Resist. Infect. Control. 2019. Vol. 8: 44.Tauch A., Schlüter A., Bischoff N., Goesmann A., Meyer F., Pühler A. The 79,370-bp conjugative plasmid pB4 consists of an IncP-1 beta backbone loaded with a chromate resistance transposon, the strA-strB streptomycin resistance gene pair, the oxacillinase gene bla(NPS-1), and a tripartite antibiotic efflux system of the resistance-nodulation-division family // Mol. Genet. Genom. 2003. Vol. 268. N 5. Р. 570–584.Tauch A., Schlüter A., Bischoff N., Goesmann A., Meyer F., Pühler A. The 79,370-bp conjugative plasmid pB4 consists of an IncP-1 beta backbone loaded with a chromate resistance transposon, the strA-strB streptomycin resistance gene pair, the oxacillinase gene bla(NPS-1), and a tripartite antibiotic efflux system of the resistance-nodulation-division family // Mol. Genet. Genom. 2003. Vol. 268. N 5. Р. 570–584.Sato T., Yokota S., Uchida I., Okubo T., Usui M., Kusumoto M., Akiba M., Fujii N., Tamura Y. Fluoroquinolone resistance mechanisms in an Escherichia coli isolate, HUE1, without quinolone resistancedetermining region mutations // Front. Microbiol. 2013. Vol. 4: 125.Sato T., Yokota S., Uchida I., Okubo T., Usui M., Kusumoto M., Akiba M., Fujii N., Tamura Y. Fluoroquinolone resistance mechanisms in an Escherichia coli isolate, HUE1, without quinolone resistancedetermining region mutations // Front. Microbiol. 2013. Vol. 4: 125.Nichols R.J., Sen S., Choo Y.J., Beltrao P., Zietek M., Chaba R., Lee S., Kazmierczak K.M., Lee K.J., Wong A., Shales M., Lovett S., Winkler M.E., Krogan N.J., Typas A., Gross C.A. Phenotypic landscape of a bacterial cell // Cell. 2011. Vol. 144. N 1. P. 143–156.Nichols R.J., Sen S., Choo Y.J., Beltrao P., Zietek M., Chaba R., Lee S., Kazmierczak K.M., Lee K.J., Wong A., Shales M., Lovett S., Winkler M.E., Krogan N.J., Typas A., Gross C.A. Phenotypic landscape of a bacterial cell // Cell. 2011. Vol. 144. N 1. P. 143–156.Bergmiller T., Andersson A.M.C., Tomasek K., Balleza E., Kiviet D.J., Hauschild R., Tkačik G., Guet C.C. Biased partitioning of the multidrug efflux pump AcrABTolC underlies long-lived phenotypic heterogeneity // Science. 2017. Vol. 356. N 6335. P. 311–315.Bergmiller T., Andersson A.M.C., Tomasek K., Balleza E., Kiviet D.J., Hauschild R., Tkačik G., Guet C.C. Biased partitioning of the multidrug efflux pump AcrABTolC underlies long-lived phenotypic heterogeneity // Science. 2017. Vol. 356. N 6335. P. 311–315.Snoussi M., Talledo J.P., Del Rosario N.A., Mohammadi S., Ha B.Y., Košmrlj A., Taheri-Araghi S. Heterogeneous absorption of antimicrobial peptide LL37 in Escherichia coli cells enhances population survivability // eLife. 2018. Vol. 7: e38174.Snoussi M., Talledo J.P., Del Rosario N.A., Mohammadi S., Ha B.Y., Košmrlj A., Taheri-Araghi S. Heterogeneous absorption of antimicrobial peptide LL37 in Escherichia coli cells enhances population survivability // eLife. 2018. Vol. 7: e38174.Wu F., Tan C. Dead bacterial absorption of antimicrobial peptides underlies collective tolerance // J. R. Soc. Interface. 2019. Vol. 16. N 151: 20180701.Wu F., Tan C. Dead bacterial absorption of antimicrobial peptides underlies collective tolerance // J. R. Soc. Interface. 2019. Vol. 16. N 151: 20180701.Bhattacharyya S., Walker D.M., Harshey R.M. Dead cells release a «necrosignal» that activates antibiotic survival pathways in bacterial swarms // Nat. Commun. 2020. Vol. 11. N. 1: 4157.Bhattacharyya S., Walker D.M., Harshey R.M. Dead cells release a «necrosignal» that activates antibiotic survival pathways in bacterial swarms // Nat. Commun. 2020. Vol. 11. N. 1: 4157.Björkholm B., Sjölund M., Falk P.G., Berg O.G., Engstrand L., Andersson D.I. Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori // Proc. Natl. Acad. Sci. U.S.A. 2001. Vol. 98. N 25. P. 14607–14612.Björkholm B., Sjölund M., Falk P.G., Berg O.G., Engstrand L., Andersson D.I. Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori // Proc. Natl. Acad. Sci. U.S.A. 2001. Vol. 98. N 25. P. 14607–14612.Long H., Miller S.F., Strauss C., Zhao C., Cheng L., Ye Z., Griffin K., Te R., Lee H., Chen C.C., Lynch M. Antibiotic treatment enhances the genome-wide mutation rate of target cells // Proc. Natl. Acad. Sci. U.S.A. 2016. Vol. 113. N 18: E2498-505.Long H., Miller S.F., Strauss C., Zhao C., Cheng L., Ye Z., Griffin K., Te R., Lee H., Chen C.C., Lynch M. Antibiotic treatment enhances the genome-wide mutation rate of target cells // Proc. Natl. Acad. Sci. U.S.A. 2016. Vol. 113. N 18: E2498-505.Reams A.B., Roth J.R. Mechanisms of gene duplication and amplification // Cold Spring Harb. Perspect. Biol. 2015. Vol. 7. N 2: a016592.Reams A.B., Roth J.R. Mechanisms of gene duplication and amplification // Cold Spring Harb. Perspect. Biol. 2015. Vol. 7. N 2: a016592.Mukherjee S., Bassler B.L. Bacterial quorum sensing in complex and dynamically changing environments // Nat. Rev. Microbiol. 2019. Vol. 17. N 6. P. 371–382.Mukherjee S., Bassler B.L. Bacterial quorum sensing in complex and dynamically changing environments // Nat. Rev. Microbiol. 2019. Vol. 17. N 6. P. 371–382.Humphries J., Xiong L., Liu J., Prindle A., Yuan F., Arjes H.A., Tsimring L., Süel G.M. Species-independent attraction to biofilms through electrical signaling // Cell. 2017. Vol. 168. N 1–2. P. 200–209.Humphries J., Xiong L., Liu J., Prindle A., Yuan F., Arjes H.A., Tsimring L., Süel G.M. Species-independent attraction to biofilms through electrical signaling // Cell. 2017. Vol. 168. N 1–2. P. 200–209.Wu H., Moser C., Wang H.Z., Høiby N., Song Z.J. Strategies for combating bacterial biofilm infections // Int. J. Oral Sci. 2015. Vol. 7. N 1. P. 1–7.Wu H., Moser C., Wang H.Z., Høiby N., Song Z.J. Strategies for combating bacterial biofilm infections // Int. J. Oral Sci. 2015. Vol. 7. N 1. P. 1–7.Sharma D., Misba L., Khan A.U. Antibiotics versus biofilm: an emerging battleground in microbial communities // Antimicrob. Resist. Infect. Control. 2019. Vol. 8: 76.Sharma D., Misba L., Khan A.U. Antibiotics versus biofilm: an emerging battleground in microbial communities // Antimicrob. Resist. Infect. Control. 2019. Vol. 8: 76.Flemming H.C., Wingender J., Szewzyk U., Steinberg P., Rice S.A., Kjelleberg S. Biofilms: an emergent form of bacterial life // Nat. Rev. Microbiol. 2016. Vol. 14. N 9. P. 563–575.Flemming H.C., Wingender J., Szewzyk U., Steinberg P., Rice S.A., Kjelleberg S. Biofilms: an emergent form of bacterial life // Nat. Rev. Microbiol. 2016. Vol. 14. N 9. P. 563–575.Wang Z., Gong X., Xie J., Xu Z., Liu G., Zhang G. Investigation of formation of bacterial biofilm upon dead siblings // Langmuir. 2019. Vol. 35. N 23. P. 7405–7413.Wang Z., Gong X., Xie J., Xu Z., Liu G., Zhang G. Investigation of formation of bacterial biofilm upon dead siblings // Langmuir. 2019. Vol. 35. N 23. P. 7405–7413.Wen X., Langevin A.M., Dunlop M.J. Antibiotic export by efflux pumps affects growth of neighboring bacteria // Sci. Rep. 2018. Vol. 8: 15120.Wen X., Langevin A.M., Dunlop M.J. Antibiotic export by efflux pumps affects growth of neighboring bacteria // Sci. Rep. 2018. Vol. 8: 15120.Lewis K. Persister cells // Annu. Rev. Microbiol. 2010. Vol. 64. P. 357–372.Lewis K. Persister cells // Annu. Rev. Microbiol. 2010. Vol. 64. P. 357–372.Nguyen D., Joshi-Datar A., Lepine F., Bauerle E., Olakanmi O., Beer K., McKay G., Siehnel R., Schafhauser J., Wang Y., Britigan B.E., Singh P.K. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria // Science. 2011. Vol. 334. N 6058. P. 982–986.Nguyen D., Joshi-Datar A., Lepine F., Bauerle E., Olakanmi O., Beer K., McKay G., Siehnel R., Schafhauser J., Wang Y., Britigan B.E., Singh P.K. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria // Science. 2011. Vol. 334. N 6058. P. 982–986.Dörr T., Vulić M., Lewis K. Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli // PLoS Biol. 2010. Vol. 8. N 2: e1000317.Dörr T., Vulić M., Lewis K. Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli // PLoS Biol. 2010. Vol. 8. N 2: e1000317.Berghoff B.A., Hoekzema M., Aulbach L., Wagner E.G. Two regulatory RNA elements affect TisBdependent depolarization and persister formation // Mol. Microbiol. 2017. Vol. 103. N 6. P. 1020–1033.Berghoff B.A., Hoekzema M., Aulbach L., Wagner E.G. Two regulatory RNA elements affect TisBdependent depolarization and persister formation // Mol. Microbiol. 2017. Vol. 103. N 6. P. 1020–1033.Edelmann D., Leinberger F.H., Schmid N.E., Oberpaul M., Schäberle T.F., Berghoff B.A. Elevated expression of toxin TisB protects persister cells against ciprofloxacin but enhances susceptibility to mitomycin C // Microorganisms. 2021. Vol. 9. N 5: 943.Edelmann D., Leinberger F.H., Schmid N.E., Oberpaul M., Schäberle T.F., Berghoff B.A. Elevated expression of toxin TisB protects persister cells against ciprofloxacin but enhances susceptibility to mitomycin C // Microorganisms. 2021. Vol. 9. N 5: 943.

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