MECHANISMS OF BACTERIAL MULTIDRUG RESISTANCE: FOCUS ON BIOCIDE-MEDIATED CROSS-RESISTANCE, GEOPOLITICAL DISSEMINATION, AND NOVEL THERAPEUTIC FRONTIERS
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.6729Keywords:
Multidrug Resistance, Efflux Pumps, Biofilms, Phage Therapy, NanomedicineAbstract
This article provides an in-depth review of the molecular mechanisms responsible for bacterial multidrug resistance (MDR), including efflux pump overexpression, enzymatic inactivation, target modification, and biofilm-associated tolerance. A structured literature search of major academic databases (PubMed, Google Scholar, and Cochrane Library) from 2010 to present was conducted to synthesize relevant molecular and clinical data. The paper analyzes epidemiological trends, the impact of geopolitical factors on MDR dissemination, and the growing burden on healthcare systems. It also evaluates current and emerging therapeutic strategies such as bacteriophage therapy, antimicrobial peptides, and efflux pump inhibitors, emphasizing translational barriers, regulatory limitations, and future research directions.
References
Centers for Disease Control and Prevention (n.d.). About antimicrobial resistance. Retrieved September 28, 2025, from https://www.cdc.gov/antimicrobial-resistance/about/index.html
World Health Organization (n.d.). Antimicrobial resistance. Retrieved September 28, 2025, from https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance
Catalano, A., Iacopetta, D., Ceramella, J., Scumaci, D., Giuzio, F., Saturnino, C., et al. (2022). Multidrug resistance (MDR): A widespread phenomenon in pharmacological therapies. Molecules, 27(3), 616. https://doi.org/10.3390/molecules27030616
Jang, S. (2023). AcrAB–TolC, a major efflux pump in Gram-negative bacteria: Toward understanding its operation mechanism. BMB Rep, 56(6), 326–334. https://doi.org/10.5483/BMBRep.2023-0070
Centers for Disease Control and Prevention (n.d.). CDC partners estimate healthcare cost of antimicrobial-resistant infections. Retrieved September 30, 2025, from https://www.cdc.gov/antimicrobial-resistance/stories/partner-estimates.html
Imai, S., Inoue, N., & Nagai, H. (2022). Economic and clinical burden from carbapenem-resistant bacterial infections and factors contributing: A retrospective study using electronic medical records in Japan. Antimicrob Resist Infect Control, 11, 108. https://doi.org/10.1186/s12879-022-07548-3
Demyanyuk, O. S., Symochko, L. Y., Vlasenko, I. S., Kashtanova, T. V., & Blenda, A. V. (2024). Antimicrobial resistance: Challenges in wartime (Ukrainian perspective). Mikrobiol Z, 86(3), 88–98. https://doi.org/10.15407/microbiolj86.03.088
Biedrzycka, M., Urbanowicz, P., Guzek, A., Brisse, S., Gniadkowski, M., & Izdebski, R. (2021). Dissemination of Klebsiella pneumoniae ST147 NDM-1 in Poland, 2015–2019. J Antimicrob Chemother, 76(10), 2538–2545. https://doi.org/10.1093/jac/dkab207
Stein, C., Zechel, M., Spott, R., Pletz, M., & Kipp, F. (2023). Multidrug-resistant isolates from Ukrainian patients in a German health facility: A genomic surveillance study focusing on antimicrobial resistance and bacterial relatedness. Infection, 51(6), 1731–1738. https://doi.org/10.1007/s15010-023-02061-4
Segundo-Arizmendi, N., Arellano-Maciel, D., Rivera-Ramírez, A., Piña-González, A. M., López-Leal, G., & Hernández-Baltazar, E. (2025). Bacteriophages: A challenge for antimicrobial therapy. Microorganisms, 13(1), 100. https://doi.org/10.3390/microorganisms13010100
Kakoullis, L., Papachristodoulou, E., Chra, P., & Panos, G. (2021). Mechanisms of antibiotic resistance in important Gram-positive and Gram-negative pathogens and novel antibiotic solutions. Antibiotics (Basel), 10(4), 415. https://doi.org/10.3390/antibiotics10040415
Almutairy, B. (2024). Extensively and multidrug-resistant bacterial strains: Case studies of antibiotics resistance. Front Microbiol, 15, 1381511. https://doi.org/10.3389/fmicb.2024.1381511
Li, X. Z., Plésiat, P., & Nikaido, H. (2015). The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev, 28(2), 337–418. https://doi.org/10.1128/CMR.00117-14
Blair, J. M., Richmond, G. E., & Piddock, L. J. (2014). Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol, 9(10), 1165–1177. https://doi.org/10.2217/fmb.14.66
Askoura, M., Mottawea, W., Abujamel, T., & Taher, I. (2011). Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa. Libyan J Med, 6, 5870. https://doi.org/10.3402/ljm.v6i0.5870
Wand, M. E., Darby, E. M., Blair, J. M., & Sutton, J. M. (2022). Contribution of the efflux pump AcrAB-TolC to the tolerance of chlorhexidine and other biocides in Klebsiella spp. J Med Microbiol, 71(3), 001496. https://doi.org/10.1099/jmm.0.001496
Kernéis, S., Lucet, J. C., Santoro, A., & Meschiari, M. (2021). Individual and collective impact of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae in patients admitted to the ICU. J Antimicrob Chemother, 76(Suppl 1), i19-i26. https://doi.org/10.1093/jac/dkaa494
Falagas, M. E., Asimotou, C. M., Zidrou, M., Kontogiannis, D. S., & Filippou, C. (2025). Global epidemiology and antimicrobial resistance of Klebsiella pneumoniae carbapenemase (KPC)-producing Gram-negative clinical isolates: A review. Microorganisms, 13(7), 1697. https://doi.org/10.3390/microorganisms13071697
Egorov, A. M., Ulyashova, M. M., & Rubtsova, M. Y. (2018). Bacterial enzymes and antibiotic resistance. Acta Naturae, 10(4), 33–48. https://doi.org/10.32607/20758251-2018-10-4-33-48
Schaenzer, A. J., & Wright, G. D. (2020). Antibiotic resistance by enzymatic modification of antibiotic targets. Trends Mol Med, 26(8), 768–782. https://doi.org/10.1016/j.molmed.2020.05.001
Kunnath, S. S., Chellappan, D. K., & Palaniveloo, K. (2024). Bacterial persister cells and development of antibiotic resistance in chronic infections: An update. Br J Biomed Sci, 81, 12958. https://doi.org/10.3389/bjbs.2024.12958
Hall, C. W., & Mah, T. F. (2017). Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria. FEMS Microbiol Rev, 41(3), 276–301. https://doi.org/10.1093/femsre/fux010
Wang, Y., & Yu, Y. (2025). Phage therapy as a revitalized weapon for treating clinical diseases. Microbiome Res Rep, 4, 35. https://doi.org/10.20517/mrr.2025.31
Alzain, M., Daghistani, H., Shamrani, T., Almoghrabi, Y., Daghistani, Y., Alharbi, O. S., et al. (2025). Antimicrobial peptides: Mechanisms, applications, and therapeutic potential. Infect Drug Resist, 18, 4385–4426. https://doi.org/10.2147/IDR.S514825
Huan, Y., Kong, Q., Mou, H., & Yi, H. (2020). Antimicrobial peptides: Classification, design, application and research progress in multiple fields. Front Microbiol, 11, 582779. https://doi.org/10.3389/fmicb.2020.582779
Compagne, N., Vieira Da Cruz, A., Müller, R. T., Hartkoorn, R. C., Flipo, M., & Pos, K. M. (2023). Update on the discovery of efflux pump inhibitors against critical priority Gram-negative bacteria. Antibiotics (Basel), 12(1), 180. https://doi.org/10.3390/antibiotics12010180
Yang, C., & Merlin, D. (2023). Challenges to safe nanomedicine treatment. Nanomaterials (Basel), 13(7), 1171. https://doi.org/10.3390/nano13071171
Tang, Z., Ma, Q., Chen, X., Chen, T., Ying, Y., Xi, X., et al. (2021). Recent advances and challenges in nanodelivery systems for antimicrobial peptides (AMPs). Antibiotics (Basel), 10(8), 990. https://doi.org/10.3390/antibiotics10080990
Musiol, R. (2023). Efflux systems as a target for anti-biofilm nanoparticles: Perspectives on emerging applications. Expert Opin Ther Targets, 27(10), 953–963. https://doi.org/10.1080/14728222.2023.2263910
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Patrycja Przebieradło, Patrycja Rędziniak, Monika Rajs, Alicja Ruzik, Antonina Gaj, Sandra Żak, Monika Kowalska, Katarzyna Żurek, Kaja Stolarska, Sandra Terpiłowska
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
