The role of uropathogenic Escherichia coli biofilms in antibiotic-resistant urinary tract infections: Nanoparticle-based, phage therapy, and quorum-sensing inhibitor approaches

Abstract

Background: Urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC) pose a global health challenge, largely due to UPEC biofilms that drive persistent infections and antibiotic resistance.

Materials and methods: To explore the role of UPEC biofilms in antibiotic-resistant UTIs and summarize emerging therapeutic strategies, this study conducted a systematic review adhering to PRISMA guidelines and registered in PROSPERO (CRD420251040212). A structured search of PubMed, Google Scholar, Scopus, and Web of Science identified English-language studies published up to 2024, with 57 eligible studies selected after three-stage screening and analyzed via thematic synthesis.

Results: This study explored UPEC biofilms enhance resistance through extracellular matrix barriers, persister cell formation, efflux pump upregulation, and horizontal gene transfer; emerging therapies including bacteriophage therapy, quorum-sensing inhibitors, and nanoparticle-based drug delivery effectively target biofilms by penetration, signaling disruption, and improved drug efficacy. Additional approaches such as antibiofilm peptides, probiotics, and immunotherapy also demonstrate potential.

Conclusions: The UPEC biofilms are key to chronic UTIs, and novel targeted therapies offer promising solutions, but clinical validation, regulatory hurdles, and combination therapy optimization are critical for translation to clinical practice.

Keywords

Uropathogenic E. coli / Biofilms / Antibiotic resistance / Bacteriophage therapy / Quorum-sensing inhibitors / Nanoparticle

Acknowledgments

None.

Statement of ethics

The review protocol followed PRISMA guidelines and was prospectively registered with the International Prospective Register of Systematic Reviews under the registration number CRD420251040212.

Conflict of interest statement

The authors declare that they have no competing interests.

Funding source

None.

Author contributions

The author was solely responsible for the entire scope of a project, from conception and design to analysis, interpretation, and writing.

Data availability

Data sharing not applicable to this article as no data-sets were generated or analyzed during the current study.

References

[1] Mancuso G, Midiri A, Gerace E, Marra M, Zummo S, Biondo C. Urinary tract infections: The current scenario and future prospects. Pathogens 2023; 12(4):623.

[2] Salam MA, Al-Amin MY, Salam MT, et al. Antimicrobial resistance: A growing serious threat for global public health. Healthcare (Basel) 2023; 11(13):1946.

[3] National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, & Committee on the Long-Term Health and Economic Effects of Antimicrobial Resistance in the United States, Palmer GH, Buckley GJ, eds. In:Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. National Academies Press; 2021: https://www.ncbi.nlm.nih.gov/books/NBK577288/. Accessed December 1, 2024.

[4] Zhou Y, Zhou Z, Zheng L, et al. Urinary tract infections caused by uropathogenic Escherichia coli: Mechanisms of infection and treatment options. Int J Mol Sci 2023; 24(13):10537.

[5] Whelan S, Lucey B, Finn K. Uropathogenic Escherichia coli (UPEC)-associated urinary tract infections: The molecular basis for challenges to effective treatment. Microorganisms 2023; 11(9):2169.

[6] Sharma S, Mohler J, Mahajan SD, Schwartz SA, Bruggemann L, Aalinkeel R. Microbial biofilm: A review on formation, infection, antibiotic resistance, control measures, and innovative treatment. Microorganisms 2023; 11(6):1614.

[7] Torres-Puig S, García V, Stærk K, et al. “Omics” technologies — What have they told us about uropathogenic Escherichia coli fitness and virulence during urinary tract infection? Front Cell Infect Microbiol 2022;12:824039.

[8] Pokharel P, Dhakal S, Dozois CM. The diversity of Escherichia coli pathotypes and vaccination strategies against this versatile bacterial pathogen. Microorganisms 2023; 11(2):344.

[9] Zhao A, Sun J, Liu Y. Understanding bacterial biofilms: From definition to treatment strategies. Front Cell Infect Microbiol 2023;13:1137947.

[10] Shree P, Singh CK, Sodhi KK, Surya JN, Singh DK. Biofilms: Understanding the structure and contribution towards bacterial resistance in antibiotics. Med Microecol 2023;16:100084.

[11] Ramírez Castillo FY, Guerrero Barrera AL, Harel J, et al. Biofilm formation by Escherichia coli isolated from urinary tract infections from Aguascalientes, Mexico. Microorganisms 2023; 11(12):2858.

[12] Shurayfan ZMM, Shubayli SIA, Maha SMA, et al. Biofilms: Mechanisms of formation and strategies for control in clinical settings. Egypt J Chem 2024; 67(13):793-816.

[13] Singh S, Datta S, Narayanan KB, Rajnish KN. Bacterial exo-polysaccharides in biofilms: Role in antimicrobial resistance and treatments. J Genet Eng Biotechnol 2021; 19(1):140.

[14] Pinto RM, Soares FA, Reis S, Nunes C, Van Dijck P. Innovative strategies toward the disassembly of the EPS matrix in bacterial biofilms. Front Microbiol 2020;11:952.

[15] Niu H, Gu J, Zhang Y. Bacterial persisters: Molecular mechanisms and therapeutic development. Signal Transduct Target Ther 2024; 9(1):174.

[16] Mayorga-Ramos A, Carrera-Pacheco SE, Barba-Ostria C, Guamán LP. Bacteriophage-mediated approaches for biofilm control. Front Cell Infect Microbiol 2024;14:1428637.

[17] Kunnath AP, Suodha Suoodh M, Chellappan DK, Chellian J, Palaniveloo K. Bacterial persister cells and development of antibiotic resistance in chronic infections: An update. Br J Biomed Sci 2024;81:12958.

[18] Ren J, Wang M, Zhou W, Liu Z. Efflux pumps as potential targets for biofilm inhibition. Front Microbiol 2024;15:1315238.

[19] Hajiagha MN, Kafil HS. Efflux pumps and microbial biofilm formation. Infect Genet Evol 2023;112:105459.

[20] Reza A, Sutton JM, Rahman KM. Effectiveness of efflux pump inhibitors as biofilm disruptors and resistance breakers in gram-negative (ESKAPEE) bacteria. Antibiotics (Basel) 2019; 8(4):229.

[21] Michaelis C, Grohmann E. Horizontal gene transfer of antibiotic resistance genes in biofilms. Antibiotics (Basel) 2023; 12(2):328.

[22] Roy S, Chowdhury G, Mukhopadhyay AK, Dutta S, Basu S. Convergence of biofilm formation and antibiotic resistance in Acinetobacter baumannii infection. Front Med (Lausanne) 2022;9:793615.

[23] Alav I, Sutton JM, Rahman KM. Role of bacterial efflux pumps in biofilm formation. J Antimicrob Chemother 2018; 73(8):2003-2020.

[24] Lila ASA, Rajab AAH, Abdallah MH, et al. Biofilm lifestyle in recurrent urinary tract infections. Life (Basel) 2023; 13(1):148.

[25] Mishra A, Aggarwal A, Khan F. Medical device-associated infections caused by biofilm-forming microbial pathogens and controlling strategies. Antibiotics (Basel) 2024; 13(7):623.

[26] Shrestha L, Fan HM, Tao HR, Huang JD. Recent strategies to combat biofilms using antimicrobial agents and therapeutic approaches. Pathogens 2022; 11(3):292.

[27] Zhou Y, Liao H, Pei L, Pu Y. Combatting persister cells: The daunting task in post-antibiotics era. Cell Insight 2023; 2(4):100104.

[28] Olawade DB, Fapohunda O, Egbon E, et al. Phage therapy: A targeted approach to overcoming antibiotic resistance. Microb Pathog 2024;197:107088.

[29] Kim BO, Kim ES, Yoo YJ, Bae HW, Chung IY, Cho YH. Phage-derived antibacterials: Harnessing the simplicity, plasticity, and diversity of phages. Viruses 2019; 11(3):268.

[30] Sionov RV, Steinberg D. Targeting the holy triangle of quorum sensing, biofilm formation, and antibiotic resistance in pathogenic bacteria. Microorganisms 2022; 10(6):1239.

[31] Juszczuk-Kubiak E. Molecular aspects of the functioning of pathogenic bacteria biofilm based on quorum sensing (QS) signal-response system and innovative non-antibiotic strategies for their elimination. Int J Mol Sci 2024; 25(5):2655.

[32] Rajkhowa S, Hussain SZ, Agarwal M, Zaheen A, Al-Hussain SA, Zaki MEA. Advancing antibiotic-resistant microbe combat: Nanocarrier-based systems in combination therapy targeting quorum sensing. Pharmaceutics 2024; 16(9):1160.

[33] Guo Y, Mao Z, Ran F, et al. Nanotechnology-based drug delivery systems to control bacterial-biofilm-associated lung infections. Pharmaceutics 2023; 15(11):2582.

[34] Aflakian F, Mirzavi F, Aiyelabegan HT, et al. Nanoparticles-based therapeutics for the management of bacterial infections: A special emphasis on FDA approved products and clinical trials. Eur J Pharm Sci 2023;188:106515.

[35] Ahsan A, Thomas N, Barnes TJ, et al. Lipid nanocarriers-enabled delivery of antibiotics and antimicrobial adjuvants to overcome bacterial biofilms. Pharmaceutics 2024; 16(3):396.

[36] Alshaikh SA, El-Banna T, Sonbol F, Farghali MH. Correlation between antimicrobial resistance, biofilm formation, and virulence determinants in uropathogenic Escherichia coli from Egyptian hospital. Ann Clin Microbiol Antimicrob 2024; 23(1):20.

[37] Oliveira M, Antunes W, Mota S, Madureira-Carvalho Á, Dinis-Oliveira RJ, Dias da Silva D. An overview of the recent advances in antimicrobial resistance. Microorganisms 2024; 12(9):1920.

[38] Kalia VC, Patel SKS, Lee JK. Bacterial biofilm inhibitors: An overview. Ecotoxicol Environ Saf 2023;264:115389.

[39] Matilla-Cuenca L, Toledo-Arana A, Valle J. Anti-biofilm molecules targeting functional amyloids. Antibiotics (Basel) 2021; 10(7):795.

[40] Al-Madboly LA, Aboulmagd A, El-Salam MA, Kushkevych I, El-Morsi RM. Microbial enzymes as powerful natural anti-biofilm candidates. Microb Cell Fact 2024; 23(1):343.

[41] Chatupheeraphat C, Peamchai J, Luk-In S, Eiamphungporn W. Synergistic effect and antibiofilm activity of the antimicrobial peptide K11 with conventional antibiotics against multidrug-resistant and extensively drug-resistant Klebsiella pneumoniae. Front Cell Infect Microbiol 2023;13:1153868.

[42] Brigida M, Saviano A, Petruzziello C, Manetti LL, Migneco A, Ojetti V. Gut microbiome implication and modulation in the management of recurrent urinary tract infection. Pathogens 2024; 13(12):1028.

[43] Dempsey E, Corr SC. Lactobacillus spp. For gastrointestinal health: Current and future perspectives. Front Immunol 2022;13:840245.

[44] Faruqui AA. Prevention and management of urinary tract infection: A non-antibiotic multi-modal approach. Int J Reprod Contracept Obstet Gynecol 2024; 13(11):3440-3447.

[45] Patel M, Siddiqui AJ, Hamadou WS, et al. Inhibition of bacterial adhesion and antibiofilm activities of a glycolipid biosurfactant from Lactobacillus rhamnosus with its physicochemical and functional properties. Antibiotics (Basel) 2021; 10(12):1546.

[46] Merenstein DJ, Tancredi DJ, Karl JP, et al. Is there evidence to support probiotic use for healthy people? Adv Nutr 2024; 15(8):100265.

[47] Yang D, Ding M, Song Y, et al. Nanotherapeutics with immunoregulatory functions for the treatment of bacterial infection. Biomater Res 2023; 27(1):73.

[48] Lopatto EDB, Santiago-Borges JM, Sanick DA, et al. Monoclonal antibodies targeting the FimH adhesin protect against uropathogenic E. coli UTI. bioRxiv 2024. doi:https://doi.org/10.1101/2024.12.10.627638.

[49] Sepulveda-Crespo D, Resino S, Martinez I. Hepatitis C virus vaccine design: Focus on the humoral immune response. J Biomed Sci 2020; 27(1):78.

[50] Filipić B, Pantelić I, Nikolić I, et al. Nanoparticle-based adjuvants and delivery systems for modern vaccines. Vaccines (Basel) 2023; 11(7):1172.

[51] Mishra S, Gupta A, Upadhye V, Singh SC, Sinha RP, Häder DP. Therapeutic strategies against biofilm infections. Life (Basel) 2023; 13(1):172.

[52] Sahoo K, Meshram S. Biofilm formation in chronic infections: A comprehensive review of pathogenesis, clinical implications, and novel therapeutic approaches. Cureus 2024; 16(10):e70629.

[53] Mirghani R, Saba T, Khaliq H, et al. Biofilms: Formation, drug resistance and alternatives to conventional approaches. AIMS Microbiol 2022; 8(3):239-277.

[54] Roy R, Tiwari M, Donelli G, Tiwari V. Strategies for combating bacterial biofilms: A focus on anti-biofilm agents and their mechanisms of action. Virulence 2018; 9(1):522-554.

[55] Tran NN, Morrisette T, Jorgensen SCJ, Orench-Benvenutti JM, Kebriaei R. Current therapies and challenges for the treatment of Staphylococcus aureus biofilm-related infections. Pharmacotherapy 2023; 43(8):816-832.

[56] Su Y, Yrastorza JT, Matis M, et al. Biofilms: Formation, research models, potential targets, and methods for prevention and treatment. Adv Sci (Weinh) 2022; 9(29):e2203291.

[57] Koo H, Allan RN, Howlin RP, Stoodley P, Hall-Stoodley L. Targeting microbial biofilms: Current and prospective therapeutic strategies. Nat Rev Microbiol 2017; 15(12):740-755.