Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC101010.15690/vramn1010MICROBIOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ МИКРОБИОЛОГИИMOLECULAR REGULATION OF PSEUDOMONAS AERUGINOSA BIOFILMSМОЛЕКУЛЯРНЫЕ СИСТЕМЫ РЕГУЛИРОВАНИЯ ФОРМИРОВАНИЯ БИОПЛЕНОК БАКТЕРИЙ PSEUDOMONAS AERUGINOSAhttps://orcid.org/0000-0002-8641-8517ManzenyukOksana Y.МанзенюкОксана Юрьевна
Russian Federation

MD, PhD.

Obolensk, Serpukhov district, Moscow region.

SPIN-код: 6871-5381

Кандидат медицинских наук, ведущий инженер-микробиолог лаборатории молекулярной биологии.

142279, Московская обл., Серпуховский район, п. Оболенск.

SPIN-код: 6871-5381

macebarron2013@gmail.comhttps://orcid.org/0000-0002-9898-9894FirstovaVictoria V.ФирстоваВиктория Валерьевна
Russian Federation

PhD.

Obolensk, Serpukhov district, Moscow region.

SPIN-код: 9166-9151

Доктор биологических наук, руководитель лаборатории молекулярной биологии.

142279, Московская обл., Серпуховский район, п. Оболенск.

SPIN-код: 9166-9151

victoria1@mai.ruhttps://orcid.org/0000-0001-5829-0512MukhinaTatiana N.МухинаТатьяна Николаевна
Russian Federation

PhD.

Obolensk, Serpukhov district, Moscow region.

SPIN-код: 6858-5052

Кандидат биологических наук, старший научный сотрудник отдела коллекционных культур.

142279, Московская обл., Серпуховский район, п. Оболенск.

SPIN-код: 6858-5052

cecile98@rambler.ruhttps://orcid.org/0000-0001-9667-1674ShemyakinIgor G.ШемякинИгорь Георгиевич
Russian Federation

PhD, Professor.

Obolensk, Serpukhov district, Moscow region.

SPIN-код: 3180-1459

Доктор биологических наук, профессор, заместитель директора по научной работе.

142279, Московская обл., Серпуховский район, п. Оболенск.

SPIN-код: 3180-1459

shemyakin@obolensk.orgFBIS State Research Center for Applied Microbiology and BiotechnologyФБУН "Государственный научный центр прикладной микробиологии и биотехнологии"060920187342442512806201828082018Copyright ©; 2018, "Paediatrician" Publishers LLCCopyright ©; 2018, Издательство "Педиатръ"2018"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/1010

Nowadays healthcare-associated infections caused Pseudomonas aeruginosa remain actual problem due to P. aeruginosa resistance to a wide range of antimicrobials and its ability to form biofilms that are 1000 times more resistant to antibiotics than free-living (plankton) cultures. P. aeruginosa biofilms forming is regulated by Quorum Sensing (QS) communication system which is controlled by inhibitors (Quorum sensing inhibitors, QSIs). An essential role in stabilization of biofilms belongs to extracellular DNA (eDNA) as a structural polyanionic polymer whereas its genetic function is not applicable. In addition, internal signal molecules c-di-GMP, cascade Gac/Rsm also participate in formation of P. aeruginosa biofilms. A review provides a detailed description of the biofilm molecular regulation by means of QS inhibitors and QS modulators of signaling molecules QS.

В настоящее время внутрибольничные инфекции, обусловленные бактериями Pseudomonas аeruginosa, продолжают оставаться актуальной проблемой ввиду устойчивости этого микроорганизма к широкому спектру антибактериальных препаратов и способности формировать биопленки, которые в 1000 раз менее чувствительны к воздействию антибиотиков, нежели свободноживущие (планктонные) культуры. Формирование биопленок P. aeruginosa регулируется коммуникационной системой «чувство кворума» (quorum sensing, QS), которая находится под контролем ингибиторов системы (QSIs). Важную роль в формировании биопленок играет внеклеточная ДНК (eDNA), структурный полианионный полимер, что само по себе является уникальным свойством, поскольку роль генетического носителя информации в данном случае не применима. Формирование биопленок P. aeruginosa регулируется также внутренними сигнальными молекулами c-di-GMP и каскадом киназ Gac/Rsm. В обзоре дано описание молекулярных механизмов действия ингибиторов сигнальных молекул системы QS, а также соединений, модулирующих сигналы QS.

Pseudomonas aeruginosabiofilmsQuorum Sensing (QS) signalsQuorum Sensing inhibitors (QSIs)Pseudomonas aeruginosaбиопленкисигналы «чувство кворума»ингибиторы системы «чувство кворума»RospotrebnadzorРоспотребнадзор1.Arivett BA, Ream DC, Fiester SE, et al. Draft genome sequences of Pseudomonas aeruginosa isolates from wounded military personne. Genome Announc. 2016;4(4)e00829-16. doi: 10.1128/genomeA.00829-16.2.Lyczak JB, Cannon CL, Pier GB. Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist. Microbes Infect. 2000;2(9):1051−1060. doi: 10.1016/s1286-4579(00)01259-4.3.Bergey DH, Holt JG. Bergey’s manual of determinative bacteriology. 9th ed. Baltimore: Williams & Wilkins; 1994.4.World Health Organization. Antibacterial agents in clinical development. An analysis of the antibacterial clinical development pipeline, including tuberculosis. Geneva: World Health Organization; 2017.5.cdc. gov [Internet]. Antibiotic Resistance Threats in the United States, 2013. Report. pp. 69−71. [cited 2018 Aug 10]. Available from: https://www.cdc.gov/drugresistance/threat-report-2013/index.html.6.Høiby N, Bjarnsholt T, Givskov M, et al. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents. 2010;35(4):322−332. doi: 10.1016/j.ijantimicag.2009.12.011.7.Van Delden C, Iglewski BH. Cell-to-cell signaling and Pseudomonas aeruginosa infections. Emerg Infect Dis. 1998;4(4):551−560. doi: 10.3201/eid0404.980405.8.Costerton JW, Lewandowski Z, Caldwell DE, et al. Microbial biofilms. Annu Rev Microbiol. 1995;49:711−745. doi: 10.1146/annurev.mi.49.100195.003431.9.Захарова Ю.А. Гнойно-септическая заболеваемость новорожденных при различных формах эпидемиологического наблюдения (выборочные исследования). // Медицинский алфавит. ― 2015. ― Т.1. ― №6 ― C. 15−18.10.Шагинян И.А., Чернуха М.Ю., Зигангирова Н.А., Гинцбург А.Л. Изучение действия субингибирующих концентраций антибиотиков на экспрессию генов, регулирующих продукцию факторов патогенности у бактерий комплекса Burkholderia cepacia и Pseudomonas aeruginosa. // Молекулярная генетика, микробиология и вирусология. ― 2005. ― №2 ― С. 13−16.11.Jacoby GA. Properties of an R plasmid in Pseudomonas aeruginosa producing amikacin (BB-K8), butirosin, kanamycin, tobramycin, and sisomicin resistance. Antimicrob Agents Chemother. 1974;6(6):807−810. doi: 10.1128/aac.6.6.807.12.Дзюбак С.Т. Механизм действия экзотоксина Pseudomonas aeruginosa на макроорганизм (экспериментальные исследования) // Журнал микробиологии. ― 1984. ― №3 ― С. 35−39.13.Gilbert P, McBain A. Potential impact of increased use of biocides in consumer products on prevalence of antibiotic resistance. Clin Microbiol Rev. 2003;16(2):189−208. doi: 10.1128/CMR.16.2.189-208.2003.14.Duan K, Surette MG. Environmental regulation of Pseudomonas aeruginosa PAO1 Las and Rhl quorum-sensing systems. J Bacteriol. 2007;189(13):4827−4836. doi: 10.1128/JB.00043-07.15.Davies DG, Parsek MR, Pearson JP, et al. The involvement of cell-to-cell signals in the development of a bacterial biofilm. Science. 1998;280(5361):295−298. doi: 10.1126/science.280.5361.295.16.O’Toole GA, Kolter R. Flagellar and twitching motility are necessary for Pseudomonas aeruginosa biofilm development. Mol Microbiol. 1998;30(2):295−304. doi: 10.1046/j.1365-2958.1998.01062.x.17.Branda SS, Vik S, Friedman L, Kolter R. Biofilms: the matrix revisited. Trends Microbiol. 2005;13(1):20−26. doi: 10.1016/j.tim.2004.11.006.18.Webb JS, Thompson LS, James S, et al. Cell death in Pseudomonas aeruginosa biofilm development. J Bacteriol. 2003;185(15):4585−4592. doi: 10.1128/jb.185.15.4585-4592.2003.19.Плакунов В.К., Мартьянов С.В., Тетенева Н.А., Журина М.В. Управление формированием микробных биопленок: анти- и пробиопленочные агенты. // Микробиология. ― 2017. ― Т.86. ― №4 ― С. 402−420.20.Banks MK, Bryers JD. Bacterial species dominance within binary culture biofilm. Appl Environ Microbiol. 1991;57(7):1974−1979.21.Allesen-Holm M, Barken KB, Yang L, et al. A characterization of DNA release in Pseudomonas aeruginosa cultures and biofilms. Mol Microbiol. 2006;59(4):1114–1128. doi: 10.1111/j.1365-2958.2005.05008.x.22.Barken KB, Pamp SJ, Yang L, et al. Roles of type IV pili, flagellum-mediated motility and extracellular DNA in the formation of mature multicellular structures in Pseudomonas aeruginosa biofilms. Environ Microbiol. 2008;10(9):2331−2343. doi: 10.1111/j.1462-2920.2008.01658.x.23.Hentzer M, Eberl L, Givskov M. Transcriptome analysis of Pseudomonas aeruginosa biofilm development: anaerobic respiration and iron limitation. Biofilms. 2005;2(1):37–61. doi: 10.1017/s1479050505001699.24.Hentzer M, Wu H, Andersen JB, et al. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J. 2003;22(15):3803−3815. doi: 10.1093/emboj/cdg366.25.Purevdorj B, Costerton JW, Stoodley P. Influence of hydrodynamics and cell signaling on the structure and behavior of Pseudomonas aeruginosa biofilms. Appl Environ Microbiol. 2002;68(9):4457−4464. doi: 10.1128/aem.68.9.4457-4464.2002.26.Bernal P, Llamas MA. Promising biotechnological applications of antibiofilm polysaccharides. Microb Biotechnol. 2012;5(6):670−673. doi: 10.1111/j.1751-7915.2012.00359.x.27.Colvin KM, Irie Y, Tart CS, et al. The Pel and Psl polysaccharides provide Pseudomonas aeruginosa structural redundancy within the biofilm matrix. Environ Microbiol. 2012;14(8):1913−1928. doi: 10.1111/j.1462-2920.2011.02657.x.28.Shak S, Capon DJ, Hellmiss R, et al. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci U S A. 1990;87(23):9188−9192. doi: 10.1073/pnas.87.23.9188.29.Chiang WC, Nilsson M, Jensen PØ, et al. Extracellular DNA shields against aminoglycosides in Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother. 2013;57(5):2352−2361. doi: 10.1128/AAC.00001-13.30.Das T, Kutty SK, Tavallaie R, et al. Phenazine virulence factor binding to extracellular DNA is important for Pseudomonas aeruginosa biofilm. Sci Rep. 2015;5:8398. doi: 10.1038/srep08398.31.Haba E, Pinazo A, Jauregui O, et al. Physicochemical characterization and antimicrobial properties of rhamnolipids produced by Pseudomonas aeruginosa 47T2 NCBIM 40044. Biotechnol Bioeng. 2003;81(3):316−322. doi: 10.1002/bit.10474.32.Alhede M, Bjarnsholt T, Jensen PØ, et al. Pseudomonas aeruginosa recognizes and responds aggressively to the presence of polymorphonuclear leukocytes. Microbiology. 2009;155(Pt 11):3500−3508. doi: 10.1099/mic.0.031443-0.33.Lee J, Wu J, Deng Y, et al. А сell-cell communication signal integrates quorum sensing and stress response. Nat Chem Biol. 2013;9(5):339−343. doi: 10.1038/nchembio.1225.34.Bjarnsholt T, Jensen PØ, Jakobsen TH, et al. Quorum sensing and virulence of Pseudomonas aeruginosa during lung infection of cystic fibrosis patients. PLoS One. 2010;5(4):e10115. doi: 10.1371/journal.pone.0010115.35.Christen M, Christen B, Folcher M, et al. Identification and characterization of a cyclic di-GMP-specific phosphodiesterase and its allosteric control by GTP. J Biol Chem. 2005;280(35):30829−30837. doi: 10.1074/jbc.M504429200.36.Düvel J, Bertinetti D, Möller S, et al. A chemical proteomics approach to identify c-di-GMP binding proteins in Pseudomonas aeruginosa. J Microbiol Methods. 2012;88(2):229−236. doi: 10.1016/j.mimet.2011.11.015.37.Borlee BR, Goldman AD, Murakami K, et al. Pseudomonas aeruginosa uses a cyclic-di-GMP-regulated adhesin to reinforce the biofilm extracellular matrix. Mol Microbiol. 2010;75(4):827−842. doi: 10.1111/j.1365-2958.2009.06991.x.38.Oglesby LL, Jain S, Ohman DE. Membrane topology and roles of Pseudomonas aeruginosa Alg8 and Alg44 in alginate polymerization. Microbiology. 2008;154(Pt 6):1605−1615. doi: 10.1099/mic.0.2007/015305-0.39.Kay E, Humair B, Dénervaud V, et al. Two GacA-dependent small RNAs modulate the quorum-sensing response in Pseudomonas aeruginosa. J Bacteriol. 2006;188(16):6026−6033. doi: 10.1128/JB.00409-06.40.Goodman AL, Merighi M, Hyodo M, et al. Direct interaction between sensor kinase proteins mediates acute and chronic disease phenotypes in a bacterial pathogen. Genes Dev. 2009;23(2):249−259. doi: 10.1101/gad.1739009.41.Chambonnier G, Roux L, Redelberger D, et al. The hybrid histidine kinase LadS forms a multicomponent signal transduction system with the GacS/GacA two-component system in Pseudomonas aeruginosa. PLoS Genet. 2016;12(5):e1006032. doi: 10.1371/journal.pgen.1006032.42.Mougous JD, Cuff ME, Raunser S, et al. A virulence locus of Pseudomonas aeruginosa encodes a protein secretion apparatus. Science. 2006;312(5779):1526−1530. doi: 10.1126/science.1128393.43.Frangipani E, Visaggio D, Heeb S, et al. The Gac/Rsm and cyclic-di-GMP signalling networks coordinately regulate iron uptake in Pseudomonas aeruginosa. Environ Microbiol. 2014;16(3):676−688. doi: 10.1111/1462-2920.12164.44.Ventre I, Goodman AL, Vallet-Gely I, et al. Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes. Proc Natl Acad Sci U S A. 2006;103(1):171−176. doi: 10.1073/pnas.0507407103.45.Moscoso JA, Jaeger T, Valentini M, et al. The diguanylate cyclase SadC is a central player in Gac/Rsm-mediated biofilm formation in Pseudomonas aeruginosa. J Bacteriol. 2014;196(23):4081−4088. doi: 10.1128/JB.01850-14.46.Hentzer M, Riedel K, Rasmussen TB, et al. Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology. 2002;148(Pt 1):87−102. doi: 10.1099/00221287-148-1-87.47.Read R, Kumar N. Production of Furanones. United States patent 20070032666 A1. 2007 Feb 8.48.Zou Y, Nair SK. Molecular basis for the recognition of structurally distinct autoinducer mimics by the Pseudomonas aeruginosa LasR quorum-sensing signaling receptor. Chem Biol. 2009;16(9):961−970. doi: 10.1016/j.chembiol.2009.09.001.49.Yang L, Rybtke MT, Jakobsen TH, et al. Computer-aided identification of recognized drugs as Pseudomonas aeruginosa quorum-sensing inhibitors. Antimicrob Agents Chemother. 2009;53(6):2432−2443. doi: 10.1128/AAC.01283-08.50.Rasmussen TB, Bjarnsholt T, Skindersoe ME, et al. Screening for quorum-sensing inhibitors (QSI) by use of a novel genetic system, the QSI selector. J Bacteriol. 2005;187(5):1799−1814. doi: 10.1128/jb.187.5.1799-1814.2005.51.Bjarnsholt T, Jensen PØ, Rasmussen TB, et al. Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology. 2005;151(Pt 12):3873−3880. doi: 10.1099/mic.0.27955-0.52.Pratt DA. Garlic and other alliums. The lore and the science. By Eric Block. Angew Chem Int Ed. 2010;49(40):7162. doi: 10.1002/anie.201004351.53.Jakobsen TH, Warming AN, Vejborg RM, et al. A broad range quorum sensing inhibitor working through sRNA inhibition. Sci Rep. 2017;7(1):9857. doi: 10.1038/s41598-017-09886-8.54.Jakobsen TH, Bragason SK, Phipps RK, et al. Food as a source for quorum sensing inhibitors: Iberin from horseradish revealed as a quorum sensing inhibitor of Pseudomonas aeruginosa. Appl Environ Microbiol. 2012;78(7):2410−2421. doi: 10.1128/AEM.05992-11.55.Tan SY, Liu Y, Chua SL, et al. Comparative systems biology analysis to study the mode of action of the isothiocyanate compound iberin on Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2014;58(11):6648−6659. doi: 10.1128/AAC.02620-13.56.Skindersoe ME, Alhede M, Phipps R, et al. Effects of antibiotics on quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2008;52(10):3648−3663. doi: 10.1128/AAC.01230-07.57.Taylor PK, Van Kessel ATM, Colavita A, et al. A novel small RNA is important for biofilm formation and pathogenicity in Pseudomonas aeruginosa. PLoS One. 2017;12(8):e0182582. doi: 10.1371/journal.pone.0182582.58.Lieberman OJ, Orr MW, Wang Y, Lee VT. High-throughput screening using the differential radial capillary action of ligand assay identifies ebselen as an inhibitor of diguanylate cyclases. ACS Chem Biol. 2014;9(1):183−192. doi: 10.1021/cb400485k.59.Zheng Y, Tsuji G, Opoku-Temeng C, Sintim HO. Inhibition of P. aeruginosa c-di-GMP phosphodiesterase RocR and swarming motility by a benzoisothiazolinone derivative. Chem Sci. 2016;7(9):6238−6244. doi: 10.1039/c6sc02103d.