Abstract
The resistance development is an increasing global health risk that needs innovative solutions. Repurposing drugs to serve as anti-virulence agents is suggested as an advantageous strategy to diminish bacterial resistance development. Bacterial virulence is controlled by quorum sensing (QS) system that orchestrates the expression of biofilm formation, motility, and virulence factors production as enzymes and virulent pigments. Interfering with QS could lead to bacterial virulence mitigation without affecting bacterial growth that does not result in bacterial resistance development. This study investigated the probable anti-virulence and anti-QS activities of α-adrenoreceptor blocker doxazosin against Proteus mirabilis and Pseudomonas aeruginosa. Besides in silico study, in vitro and in vivo investigations were conducted to assess the doxazosin anti-virulence actions. Doxazosin significantly diminished the biofilm formation and release of QS-controlled Chromobacterium violaceum pigment and virulence factors in P. aeruginosa and P. mirabilis, and downregulated the QS encoding genes in P. aeruginosa. Virtually, doxazosin interfered with QS proteins, and in vivo protected mice against P. mirabilis and P. aeruginosa. The role of the membranal sensors as QseC and PmrA was recognized in enhancing the Gram-negative virulence. Doxazosin downregulated the membranal sensors PmR and QseC encoding genes and could in silico interfere with them. In conclusion, this study preliminary documents the probable anti-QS and anti-virulence activities of doxazosin, which indicate its possible application as an alternative or in addition to antibiotics. However, extended toxicological and pharmacological investigations are essential to approve the feasible clinical application of doxazosin as novel efficient anti-virulence agent.
Key points
• Anti-hypertensive doxazosin acquires anti-quorum sensing activities
• Doxazosin diminishes the virulence of Proteus mirabilis and Pseudomonas aeruginosa
• Doxazosin could dimmish the bacterial espionage
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Data availability
All data generated or analyzed during this study are included in the submitted manuscript.
References
Abbas HA, Hegazy WAH (2017) Targeting the virulence factors of Serratia marcescens by ambroxol. Roum Arch Microbiol Immunol 76(2):27–32
Abbas HA, Hegazy WAH (2020) Repurposing anti-diabetic drug “Sitagliptin” as a novel virulence attenuating agent in Serratia marcescens. PLoS One 15(4):e0231625. https://doi.org/10.1371/journal.pone.0231625
Abisado RG, Benomar S, Klaus JR, Dandekar AA, Chandler JR (2018) Bacterial quorum sensing and microbial community interactions. mBio 9(3) https://doi.org/10.1128/mBio.02331-17
Agha KA, Abo-Dya NE, Ibrahim TS, Abdel-Aal EH, Hegazy WA (2016) Benzotriazole-mediated synthesis and antibacterial activity of novel N-Acylcephalexins. Sci Pharm 84(3):484–496. https://doi.org/10.3390/scipharm84030484
Aldawsari MF, Khafagy ES, Saqr AA, Alalaiwe A, Abbas HA, Shaldam MA, Hegazy WAH, Goda RM (2021) Tackling virulence of Pseudomonas aeruginosa by the natural furanone sotolon. Antibiotics (Basel) 10(7) https://doi.org/10.3390/antibiotics10070871
Almalki AJ, Ibrahim TS, Elhady SS, Darwish KM, Hegazy WAH (2022a) Repurposing α-adrenoreceptor blockers as promising anti-virulence agents in gram-negative bacteria. Antibiotics 11(2):178. https://doi.org/10.3390/antibiotics11020178
Almalki AJ, Ibrahim TS, Elhady SS, Hegazy WAH, Darwish KM (2022b) Computational and biological evaluation of β-adrenoreceptor blockers as promising bacterial anti-virulence agents. Pharmaceuticals 15(2):110. https://doi.org/10.3390/ph15020110
Almalki AJ, Ibrahim TS, Taher ES, Mohamed MFA, Youns M, Hegazy WAH, Al-Mahmoudy AMM (2022c) Synthesis, antimicrobial, anti-virulence and anticancer evaluation of new 5(4H)-oxazolone-based sulfonamides. Molecules 27(3):671. https://doi.org/10.3390/molecules27030671
Ang S, Horng YT, Shu JC, Soo PC, Liu JH, Yi WC, Lai HC, Luh KT, Ho SW, Swift S (2001) The role of RsmA in the regulation of swarming motility in Serratia marcescens. J Biomed Sci 8(2):160–169. https://doi.org/10.1007/BF02256408
Armbruster CE, Mobley HL (2012) Merging mythology and morphology: the multifaceted lifestyle of Proteus mirabilis. Nat Rev Microbiol 10(11):743–754. https://doi.org/10.1038/nrmicro2890
Askoura M, Almalki AJ, Lila ASA, Almansour K, Alshammari F, Khafagy E-S, Ibrahim TS, Hegazy WAH (2021) Alteration of Salmonella enterica virulence and host pathogenesis through targeting sdiA by using the CRISPR-Cas9 system. Microorganisms 9(12):2564. https://doi.org/10.3390/microorganisms9122564
Askoura M, Hegazy WAH (2020) Ciprofloxacin interferes with Salmonella Typhimurium intracellular survival and host virulence through repression of Salmonella pathogenicity island-2 (SPI-2) genes expression. Pathog Dis 78(1) https://doi.org/10.1093/femspd/ftaa011
Bjarnsholt T, Jensen PO, Jakobsen TH, Phipps R, Nielsen AK, Rybtke MT, Tolker-Nielsen T, Givskov M, Hoiby N, Ciofu O, Scandinavian Cystic Fibrosis Study C (2010) Quorum sensing and virulence of Pseudomonas aeruginosa during lung infection of cystic fibrosis patients. PLoS One 5(4):e10115. https://doi.org/10.1371/journal.pone.0010115
Boibessot T, Zschiedrich CP, Lebeau A, Benimelis D, Dunyach-Remy C, Lavigne JP, Szurmant H, Benfodda Z, Meffre P (2016) The rational design, synthesis, and antimicrobial properties of thiophene derivatives that inhibit bacterial histidine kinases. J Med Chem 59(19):8830–8847. https://doi.org/10.1021/acs.jmedchem.6b00580
Brackman G, Cos P, Maes L, Nelis HJ, Coenye T (2011) Quorum sensing inhibitors increase the susceptibility of bacterial biofilms to antibiotics in vitro and in vivo. Antimicrob Agents Chemother 55:2655–2661. https://doi.org/10.1128/AAC.00045-11
Carabajal MA, Asquith CRM, Laitinen T, Tizzard GJ, Yim L, Rial A, Chabalgoity JA, Zuercher WJ, Garcia Vescovi E (2019) Quinazoline-based antivirulence compounds selectively target Salmonella PhoP/PhoQ signal transduction system. Antimicrob Agents Chemother 64(1) https://doi.org/10.1128/AAC.01744-19
Cavalu S, Elbaramawi SS, Eissa AG, Radwan MF, Ibrahim ST, Khafagy E-S, Lopes BS, Ali MAM, Hegazy WAH, Elfaky MA (2022) Characterization of the anti-biofilm and anti-quorum sensing activities of the β-adrenoreceptor antagonist atenolol against gram-negative bacterial pathogens. Int J Mol Sci 23(21):13088. https://doi.org/10.3390/ijms232113088
Chen G, Swem LR, Swem DL, Stauff DL, O’Loughlin CT, Jeffrey PD, Bassler BL, Hughson FM (2011) A strategy for antagonizing quorum sensing. Mol Cell 42(2):199–209. https://doi.org/10.1016/j.molcel.2011.04.003
Cornelis GR (2006) The type III secretion injectisome. Nat Rev Microbiol 4(11):811–825. https://doi.org/10.1038/nrmicro1526
Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717. https://doi.org/10.1038/srep42717
Dell’Omo G, Penno G, Del Prato S, Pedrinelli R (2007) Doxazosin in metabolically complicated hypertension. Expert Rev Cardiovasc Ther 5(6):1027–1035. https://doi.org/10.1586/14779072.5.6.1027
Deng Y, Xu H, Su Y, Liu S, Xu L, Guo Z, Wu J, Cheng C, Feng J (2019) Horizontal gene transfer contributes to virulence and antibiotic resistance of Vibrio harveyi 345 based on complete genome sequence analysis. BMC Genomics 20(1):761. https://doi.org/10.1186/s12864-019-6137-8
Denton M, Kerr K, Mooney L, Keer V, Rajgopal A, Brownlee K, Arundel P, Conway S (2002) Transmission of colistin-resistant Pseudomonas aeruginosa between patients attending a pediatric cystic fibrosis center. Pediatr Pulmonol 34(4):257–261. https://doi.org/10.1002/ppul.10166
El-Mowafy SA, Shaaban MI, Abd El Galil KH (2014) Sodium ascorbate as a quorum sensing inhibitor of Pseudomonas aeruginosa. J Appl Microbiol 117(5):1388–1399. https://doi.org/10.1111/jam.12631
Filloux A (2011) Protein secretion systems in Pseudomonas aeruginosa: an essay on diversity, evolution, and function. Front Microbiol 2:155. https://doi.org/10.3389/fmicb.2011.00155
Francis VI, Stevenson EC, Porter SL (2017) Two-component systems required for virulence in Pseudomonas aeruginosa. FEMS Microbiol Lett 364(11) https://doi.org/10.1093/femsle/fnx104
Garcia-Contreras R (2016) Is quorum sensing interference a viable alternative to treat Pseudomonas aeruginosa infections? Front Microbiol 7:1454. https://doi.org/10.3389/fmicb.2016.01454
Garcia-Contreras R, Nunez-Lopez L, Jasso-Chavez R, Kwan BW, Belmont JA, Rangel-Vega A, Maeda T, Wood TK (2015) Quorum sensing enhancement of the stress response promotes resistance to quorum quenching and prevents social cheating. ISME J 9(1):115–125. https://doi.org/10.1038/ismej.2014.98
Gaynes R, Edwards JR, National Nosocomial Infections Surveillance S (2005) Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis: an Official Publication of the Infectious Diseases Society of America 41(6):848–854. https://doi.org/10.1086/432803
Gellatly SL, Hancock RE (2013) Pseudomonas aeruginosa: new insights into pathogenesis and host defenses. Pathog Dis 67(3):159–173. https://doi.org/10.1111/2049-632X.12033
Gilmour R, Foster JE, Sheng Q, McClain JR, Riley A, Sun PM, Ng WL, Yan D, Nicas TI, Henry K, Winkler ME (2005) New class of competitive inhibitor of bacterial histidine kinases. J Bacteriol 187(23):8196–8200. https://doi.org/10.1128/JB.187.23.8196-8200.2005
Gooderham WJ, Hancock RE (2009) Regulation of virulence and antibiotic resistance by two-component regulatory systems in Pseudomonas aeruginosa. FEMS Microbiol Rev 33(2):279–294. https://doi.org/10.1111/j.1574-6976.2008.00135.x
Guarnieri MT, Zhang L, Shen J, Zhao R (2008) The Hsp90 inhibitor radicicol interacts with the ATP-binding pocket of bacterial sensor kinase PhoQ. J Mol Biol 379(1):82–93. https://doi.org/10.1016/j.jmb.2008.03.036
Harrison AM, Soby SD (2020) Reclassification of Chromobacterium violaceum ATCC 31532 and its quorum biosensor mutant CV026 to Chromobacterium subtsugae. AMB Express 10(1):202. https://doi.org/10.1186/s13568-020-01140-1
Hegazy WAH (2016) Diclofenac inhibits virulence of Proteus mirabilis isolated from diabetic foot ulcer. Afr J Microbiol Res 10(21):733–743. https://doi.org/10.5897/AJMR2016.8043
Hegazy WAH, Abbas HA (2017) Evaluation of the role of SsaV ‘Salmonella pathogenicity island-2 dependent type III secretion system components on the virulence behavior of Salmonella enterica serovar Typhimurium. Afr J Biotechnol 16(14):718–726. https://doi.org/10.5897/AJB2016.15852
Hegazy WAH, Khayat MT, Ibrahim TS, Youns M, Mosbah R, Soliman WE (2021a) Repurposing of antidiabetics as Serratia marcescens virulence inhibitors. Braz J Microbiol 52(2):627–638. https://doi.org/10.1007/s42770-021-00465-8
Hegazy WAH, Rajab AAH, Abu Lila AS, Abbas HA (2021b) Anti-diabetics and antimicrobials: harmony of mutual interplay. World J Diabetes 12(11):1832–1855. https://doi.org/10.4239/wjd.v12.i11.1832
Hegazy WAH, Salem IM, Alotaibi HF, Khafagy E-S, Ibrahim D (2022) Terazosin interferes with quorum sensing and type three secretion system and diminishes the bacterial espionage to mitigate the Salmonella typhimurium pathogenesis. Antibiotics 11(4):465. https://doi.org/10.3390/antibiotics11040465
Hegazy WAH, Khayat MT, Ibrahim TS, Nassar MS, Bakhrebah MA, Abdulaal WH, Alhakamy NA, Bendary MM (2020) Repurposing anti-diabetic drugs to cripple quorum sensing in Pseudomonas aeruginosa. Microorganisms 8(9) https://doi.org/10.3390/microorganisms8091285
Hentzer M, Wu H, Andersen JB, Riedel K, Rasmussen TB, Bagge N, Kumar N, Schembri MA, Song Z, Kristoffersen P, Manefield M, Costerton JW, Molin S, Eberl L, Steinberg P, Kjelleberg S, Hoiby N, Givskov M (2003) Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J 22(15):3803–3815. https://doi.org/10.1093/emboj/cdg366
Horcajada JP, Montero M, Oliver A, Sorli L, Luque S, Gomez-Zorrilla S, Benito N, Grau S (2019) Epidemiology and treatment of multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa infections. Clin Microbiol Rev 32(4) https://doi.org/10.1128/CMR.00031-19
Jiang T, Li M (2013) Quorum sensing inhibitors: a patent review. Expert Opin Ther Pat 23(7):867–94. https://doi.org/10.1517/13543776.2013.779674
Jiang Q, Chen J, Yang C, Yin Y, Yao K (2019) Quorum sensing: a prospective therapeutic target for bacterial diseases. Biomed Res Int 2019:2015978. https://doi.org/10.1155/2019/2015978
Jiang W, Ubhayasekera W, Breed MC, Norsworthy AN, Serr N, Mobley HLT, Pearson MM, Knight SD (2020) MrpH, a new class of metal-binding adhesin, requires zinc to mediate biofilm formation. PLoS Pathog 16(8):e1008707. https://doi.org/10.1371/journal.ppat.1008707
Juhas M, Eberl L, Tummler B (2005) Quorum sensing: the power of cooperation in the world of Pseudomonas. Environ Microbiol 7(4):459–471. https://doi.org/10.1111/j.1462-2920.2005.00769.x
Kalia VC, Purohit HJ (2011) Quenching the quorum sensing system: potential antibacterial drug targets. Crit Rev Microbiol 37(2):121–140. https://doi.org/10.3109/1040841X.2010.532479
Karavolos MH, Winzer K, Williams P, Khan CM (2013) Pathogen espionage: multiple bacterial adrenergic sensors eavesdrop on host communication systems. Mol Microbiol 87(3):455–465. https://doi.org/10.1111/mmi.12110
Khayat MT, Abbas HA, Ibrahim TS, Khayyat AN, Alharbi M, Darwish KM, Elhady SS, Khafagy E-S, Safo MK, Hegazy WAH (2022a) Anti-quorum sensing activities of gliptins against Pseudomonas aeruginosa and Staphylococcus aureus. Biomedicines 10(5):1169. https://doi.org/10.3390/biomedicines10051169
Khayat MT, Ibrahim TS, Khayyat AN, Alharbi M, Shaldam MA, Mohammad KA, Khafagy E-S, El-damasy DA, Hegazy WAH, Abbas HA (2022b) Sodium citrate alleviates virulence in Pseudomonas aeruginosa. Microorganisms 10(5):1046. https://doi.org/10.3390/microorganisms10051046
Khayyat AN, Abbas HA, Khayat MT, Shaldam MA, Askoura M, Asfour HZ, Khafagy E-S, Abu Lila AS, Allam AN, Hegazy WAH (2021a) Secnidazole is a promising imidazole mitigator of Serratia marcescens virulence. Microorganisms 9(11):2333. https://doi.org/10.3390/microorganisms9112333
Khayyat AN, Abbas HA, Mohamed MFA, Asfour HZ, Khayat MT, Ibrahim TS, Youns M, Khafagy E-S, Abu Lila AS, Safo MK, Hegazy WAH (2021b) Not only antimicrobial: metronidazole mitigates the virulence of Proteus mirabilis isolated from macerated diabetic foot ulcer. Appl Sci 11(15):6847. https://doi.org/10.3390/app11156847
Khayyat AN, Hegazy WAH, Shaldam MA, Mosbah R, Almalki AJ, Ibrahim TS, Khayat MT, Khafagy ES, Soliman WE, Abbas HA (2021c) Xylitol inhibits growth and blocks virulence in Serratia marcescens. Microorganisms 9(5) https://doi.org/10.3390/microorganisms9051083
Kim W, Surette MG (2006) Coordinated regulation of two independent cell-cell signaling systems and swarmer differentiation in Salmonella enterica serovar Typhimurium. J Bacteriol 188(2):431–440. https://doi.org/10.1128/JB.188.2.431-440.2006
Kim T, Duong T, Wu CA, Choi J, Lan N, Kang SW, Lokanath NK, Shin D, Hwang HY, Kim KK (2014) Structural insights into the molecular mechanism of Escherichia coli SdiA, a quorum-sensing receptor. Acta Crystallogr D Biol Crystallogr 70(Pt 3):694–707. https://doi.org/10.1107/S1399004713032355
Kim HS, Lee SH, Byun Y, Park HD (2015) 6-Gingerol reduces Pseudomonas aeruginosa biofilm formation and virulence via quorum sensing inhibition. Sci Rep 5:8656. https://doi.org/10.1038/srep08656
Li J, Turnidge J, Milne R, Nation RL, Coulthard K (2001) In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother 45(3):781–785. https://doi.org/10.1128/AAC.45.3.781-785.2001
Liaw SJ, Lai HC, Ho SW, Luh KT, Wang WB (2003) Role of RsmA in the regulation of swarming motility and virulence factor expression in Proteus mirabilis. J Med Microbiol 52(Pt 1):19–28. https://doi.org/10.1099/jmm.0.05024-0
Lim SM, Webb SA (2005) Nosocomial bacterial infections in Intensive Care Units I: Organisms and mechanisms of antibiotic resistance. Anaesthesia 60(9):887–902. https://doi.org/10.1111/j.1365-2044.2005.04220.x
Lintz MJ, Oinuma K, Wysoczynski CL, Greenberg EP, Churchill ME (2011) Crystal structure of QscR, a Pseudomonas aeruginosa quorum sensing signal receptor. Proc Natl Acad Sci USA 108(38):15763–15768. https://doi.org/10.1073/pnas.1112398108
Livermore DM, British Society for Antimicrobial Chemotherapy Working Party on The Urgent Need: Regenerating Antibacterial Drug D, Development (2011) Discovery research: the scientific challenge of finding new antibiotics. J Antimicrob Chemother 66(9):1941–4. https://doi.org/10.1093/jac/dkr262
Ma DL, Chan DS, Leung CH (2013) Drug repositioning by structure-based virtual screening. Chem Soc Rev 42(5):2130–2141. https://doi.org/10.1039/c2cs35357a
Mackay M, Milne K, Gould I (2000) Comparison of methods for assessing synergic antibiotic interactions. Int J Antimicrob Agents 15(2):125–129. https://doi.org/10.1016/S0924-8579(00)00149-7
Medzhitov R (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1(2):135–145. https://doi.org/10.1038/35100529
Methner U, Rabsch W, Reissbrodt R, Williams PH (2008) Effect of norepinephrine on colonisation and systemic spread of Salmonella enterica in infected animals: role of catecholate siderophore precursors and degradation products. Int J Med Microbiol 298(5–6):429–439. https://doi.org/10.1016/j.ijmm.2007.07.013
Mohr KI (2016) History of antibiotics research. Curr Top Microbiol Immunol 398:237–272. https://doi.org/10.1007/82_2016_499
Morata L, Cobos-Trigueros N, Martinez JA, Soriano A, Almela M, Marco F, Sterzik H, Nunez R, Hernandez C, Mensa J (2012) Influence of multidrug resistance and appropriate empirical therapy on the 30-day mortality rate of Pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother 56(9):4833–4837. https://doi.org/10.1128/AAC.00750-12
Moreira CG, Russell R, Mishra AA, Narayanan S, Ritchie JM, Waldor MK, Curtis MM, Winter SE, Weinshenker D, Sperandio V (2016) Bacterial adrenergic sensors regulate virulence of enteric pathogens in the gut. mBio 7(3) https://doi.org/10.1128/mBio.00826-16
Moreira CG, Sperandio V (2012) Interplay between the QseC and QseE bacterial adrenergic sensor kinases in Salmonella enterica serovar Typhimurium pathogenesis. Infect Immun 80(12):4344–4353. https://doi.org/10.1128/IAI.00803-12
Moskowitz SM, Ernst RK, Miller SI (2004) PmrAB, a two-component regulatory system of Pseudomonas aeruginosa that modulates resistance to cationic antimicrobial peptides and addition of aminoarabinose to lipid A. J Bacteriol 186(2):575–579. https://doi.org/10.1128/JB.186.2.575-579.2004
Muhlen S, Dersch P (2016) Anti-virulence strategies to target bacterial infections. Curr Top Microbiol Immunol 398:147–183. https://doi.org/10.1007/82_2015_490
Nalca Y, Jansch L, Bredenbruch F, Geffers R, Buer J, Haussler S (2006) Quorum-sensing antagonistic activities of azithromycin in Pseudomonas aeruginosa PAO1: a global approach. Antimicrob Agents Chemother 50(5):1680–1688. https://doi.org/10.1128/AAC.50.5.1680-1688.2006
Ohman DE, Cryz SJ, Iglewski BH (1980) Isolation and characterization of Pseudomonas aeruginosa PAO mutant that produces altered elastase. J Bacteriol 142(3):836–842. https://doi.org/10.1128/jb.142.3.836-842.1980
Okada BK, Li A, Seyedsayamdost MR (2019) Identification of the hypertension drug guanfacine as an antivirulence agent in Pseudomonas aeruginosa. ChemBioChem 20(15):2005–2011. https://doi.org/10.1002/cbic.201900129
Pawar S, Ashraf MI, Mujawar S, Mishra R, Lahiri C (2018) In silico identification of the indispensable quorum sensing proteins of multidrug resistant Proteus mirabilis. Front Cell Infect Microbiol 8:269. https://doi.org/10.3389/fcimb.2018.00269
Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18(1):41–58. https://doi.org/10.1038/nrd.2018.168
Rasko DA, Sperandio V (2010) Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov 9(2):117–128. https://doi.org/10.1038/nrd3013
Rasko DA, Moreira CG, de Li R, Reading NC, Ritchie JM, Waldor MK, Williams N, Taussig R, Wei S, Roth M, Hughes DT, Huntley JF, Fina MW, Falck JR, Sperandio V (2008) Targeting QseC signaling and virulence for antibiotic development. Science 321(5892):1078–1080. https://doi.org/10.1126/science.1160354
Rather PN (2005) Swarmer cell differentiation in Proteus mirabilis. Environ Microbiol 7(8):1065–1073. https://doi.org/10.1111/j.1462-2920.2005.00806.x
Reading NC, Rasko DA, Torres AG, Sperandio V (2009) The two-component system QseEF and the membrane protein QseG link adrenergic and stress sensing to bacterial pathogenesis. Proc Natl Acad Sci USA 106(14):5889–5894. https://doi.org/10.1073/pnas.0811409106
Rozalski A, Sidorczyk Z, Kotelko K (1997) Potential virulence factors of Proteus bacilli. Microbiol Mol Biol Rev 61(1):65–89. https://doi.org/10.1128/mmbr.61.1.65-89.1997
Sanz-Garcia F, Hernando-Amado S, Martinez JL (2018) Mutational evolution of Pseudomonas aeruginosa resistance to ribosome-targeting antibiotics. Front Genet 9:451. https://doi.org/10.3389/fgene.2018.00451
Saqr AA, Aldawsari MF, Khafagy E-S, Shaldam MA, Hegazy WAH, Abbas HA (2021) A novel use of allopurinol as a quorum-sensing inhibitor in Pseudomonas aeruginosa. Antibiotics 10(11):1385. https://doi.org/10.3390/antibiotics10111385
Schneider R, Lockatell CV, Johnson D, Belas R (2002) Detection and mutation of a luxS-encoded autoinducer in Proteus mirabilis. Microbiology (reading) 148(Pt 3):773–782. https://doi.org/10.1099/00221287-148-3-773
Sekhar S, Vyas N, Unnikrishnan M, Rodrigues G, Mukhopadhyay C (2014) Antimicrobial susceptibility pattern in diabetic foot ulcer: a pilot study. Ann Med Health Sci Res 4(5):742–745. https://doi.org/10.4103/2141-9248.141541
Thabit AK, Eljaaly K, Zawawi A, Ibrahim TS, Eissa AG, Elbaramawi SS, Hegazy WAH, Elfaky MA (2022) Muting bacterial communication: evaluation of prazosin anti-quorum sensing activities against gram-negative bacteria Pseudomonas aeruginosa, Proteus mirabilis, and Serratia marcescens. Biol 11(1349 11):1349. https://doi.org/10.3390/BIOLOGY11091349
Thabit AK, Eljaaly K, Zawawi A, Ibrahim TS, Eissa AG, Elbaramawi SS, Hegazy WAH, Elfaky MA (2022a) Silencing of Salmonella typhimurium pathogenesis: atenolol acquires efficient anti-virulence activities. Microorganisms 10(10) https://doi.org/10.3390/microorganisms10101976
Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, Yuan D, Stroe O, Wood G, Laydon A, Zidek A, Green T, Tunyasuvunakool K, Petersen S, Jumper J, Clancy E, Green R, Vora A, Lutfi M, Figurnov M, Cowie A, Hobbs N, Kohli P, Kleywegt G, Birney E, Hassabis D, Velankar S (2022) AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high- accuracy models. Nucleic Acids Res 50(D1):D439–D444. https://doi.org/10.1093/nar/gkab1061
Wykretowicz A, Guzik P, Wysocki H (2008) Doxazosin in the current treatment of hypertension. Expert Opin Pharmacother 9(4):625–633. https://doi.org/10.1517/14656566.9.4.625
Xie W, Dickson C, Kwiatkowski W, Choe S (2010) Structure of the cytoplasmic segment of histidine kinase receptor QseC, a key player in bacterial virulence. Protein Pept Lett 17(11):1383–1391. https://doi.org/10.2174/0929866511009011383
Youns M, Askoura M, Abbas HA, Attia GH, Khayyat AN, Goda RM, Almalki AJ, Khafagy ES, Hegazy WAH (2021) Celastrol modulates multiple signaling pathways to inhibit proliferation of pancreatic cancer via DDIT3 and ATF3 up-regulation and RRM2 and MCM4 down-regulation. Onco Targets Ther 14:3849–3860. https://doi.org/10.2147/OTT.S313933
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This research work was funded by Institutional Fund Projects under grant no. (IFPIP:1623-166-1443). The authors gratefully acknowledge technical and financial support provided by the Ministry of Education and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.
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This research work was funded by Institutional Fund Projects under grant no. (IFPIP:1623–166-1443).
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MAE, TSI, and WAHH conceived, designed the study, and analyzed data. WAAH, SSE, and AGE analyzed the data and wrote the first draft of this manuscript. ESK and MAMA did the software and wrote the final version of the manuscript. All authors read and approved the manuscript.
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Elfaky, M.A., Elbaramawi, S.S., Eissa, A.G. et al. Drug repositioning: doxazosin attenuates the virulence factors and biofilm formation in Gram-negative bacteria. Appl Microbiol Biotechnol 107, 3763–3778 (2023). https://doi.org/10.1007/s00253-023-12522-3
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DOI: https://doi.org/10.1007/s00253-023-12522-3