Main Article Content

Abstract

Antibiotic resistance is a widespread problem that reduces the effectiveness of antibiotics, leading the rise of multidrug resistance (MDR). Efflux pump, biofilm formation and plasmid based gene transfer together form the basis of co-adaptive mechanisms providing fleeting tolerance resistant overtime. Genes encoding efflux systems are alternative efflux-pumping systems that remove some antimicrobial agents, so that over extremely low intracellular concentrations are required for the bacterium to survive in the biofilm matrix.These, in turn, contribute to the structural and functional coherence of biofilms, which serve as protected niches favoring horizontal gene transfer and the propagation of plasmid-mediated resistance genes. In this review, we combine recent data from molecular and omics-based studies to demonstrate how these systems are co-regulated to control resistance in bacteria, with an emphasis on cross-talk between regulatory pathways including quorum-sensing, stress-response signalling and global transcriptional regulators. Insights into this interplay can pave the way for innovative therapeutic strategies, such as efflux pump inhibitors, biofilm dispersal agents and plasmid-curing strategies. Comprehensive knowledge of these interrelated processes may influence the development of future antimicrobial agents and their use, and may reduce the emergence of pan-resistant species of bacterial pathogens.

Keywords

Antimicrobial resistance Bacterial resistance Efflux pumps Biofilms Plasmids Horizontal gene transfer

Article Details

How to Cite
Mohammed, Z. (2025) “An integrated view of bacterial resistance in the antibiotic era: efflux pumps biofilms and plasmids”, Journal of Biomedicine and Biochemistry, 4(4), pp. 97–107. doi:10.57238/jbb.2025.7432.1159.

How to Cite

Mohammed, Z. (2025) “An integrated view of bacterial resistance in the antibiotic era: efflux pumps biofilms and plasmids”, Journal of Biomedicine and Biochemistry, 4(4), pp. 97–107. doi:10.57238/jbb.2025.7432.1159.

References

  1. Murray CJL, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-655. https://doi.org/10.1016/S0140-6736(21)02724-0.
  2. Nair RR, Andersson DI, Warsi OM. Antibiotic resistance begets more resistance: chromosomal resistance mutations mitigate fitness costs conferred by multi-resistant clinical plasmids. Microbiol Spectr. 2024;12(5):e0420623. https://doi.org/10.1128/spectrum.04206-23.
  3. Elshobary ME, et al. Combating antibiotic resistance: mechanisms, multidrug-resistant pathogens, and novel therapeutic approaches. Pharmaceuticals (Basel). 2025;18(3):402.
  4. Li XZ, Nikaido H. Efflux-mediated drug resistance in bacteria: an update. Drugs. 2009;69(12):1555-1623. https://doi.org/10.2165/11317030-000000000-00000.
  5. Khan J, et al. Challenges of antibiotic resistance biofilms and potential combating strategies. 3 Biotech. 2021;11(4):169. https://doi.org/10.1007/s13205-021-02707-w.
  6. Michaelis C, Grohmann E. Horizontal gene transfer of antibiotic resistance genes in biofilms. Antibiotics (Basel). 2023;12(2):328. https://doi.org/10.3390/antibiotics12020328.
  7. Li L, et al. Relationship between biofilm formation and antibiotic resistance of Klebsiella pneumoniae. Front Cell Infect Microbiol. 2024;14:1324895. https://doi.org/10.3389/fcimb.2024.1324895.
  8. Gaurav A, et al. Role of bacterial efflux pumps in antibiotic resistance and virulence. Microbiology (Reading). 2023;169(5):001333. https://doi.org/10.1099/mic.0.001333.
  9. Sharma A, Gupta VK, Pathania R. Efflux pump inhibitors for bacterial pathogens. Indian J Med Res. 2019;149(2):129-145. https://doi.org/10.4103/ijmr.IJMR_2079_17.
  10. Andersen JL, et al. Multidrug efflux pumps from food pathogens. Int J Environ Res Public Health. 2015;12(2):1487-1547.
  11. Routh MD, et al. Efflux pumps of the RND family. Adv Enzymol Relat Areas Mol Biol. 2011;77:109-146. https://doi.org/10.1002/9780470920541.ch3.
  12. Reddy VS, et al. The major facilitator superfamily revisited. FEBS J. 2012;279(11):2022-2035. https://doi.org/10.1111/j.1742-4658.2012.08588.x.
  13. Burata OE, et al. Small multidrug resistance transporter family. J Biol Chem. 2022;298(10):102482. https://doi.org/10.1016/j.jbc.2022.102482.
  14. How SS, et al. ATP-binding cassette transporters in bacterial pathogenesis. J Zhejiang Univ Sci B. 2024;26(1):58-75. https://doi.org/10.1631/jzus.B2300641.
  15. Maldonado J, et al. Efflux pump regulator AcrR represses motility in E. coli. mSphere. 2023;8(5):e0043023. https://doi.org/10.1128/msphere.00430-23.
  16. Novelli M, Bolla JM. RND efflux pump induction. Antibiotics (Basel). 2024;13(6):501.
  17. Dawan J, Ahn J. Bacterial stress responses and antibiotic resistance. Microorganisms. 2022;10(7):1385.https://doi.org/10.3390/microorganisms10071385.
  18. Zhang L, et al. Bacterial efflux pump inhibitors reduce resistance. Pharmaceutics. 2024;16(2):170. https://doi.org/10.3390/pharmaceutics16020170.
  19. Plasencia-Rebata S, et al. Effect of PAβN on MICs in A. baumannii. Antibiotics (Basel). 2023;12(6):1071. https://doi.org/10.3390/antibiotics12061071.
  20. Reza A, Sutton JM, Rahman KM. Efflux pump inhibitors as resistance breakers. Antibiotics (Basel). 2019;8(4):229. https://doi.org/10.3390/antibiotics8040229.
  21. Soto SM. Role of efflux pumps in biofilm resistance. Virulence. 2013;4(3):223-229. https://doi.org/10.4161/viru.23724.
  22. Van Acker H, Coenye T. Efflux and physiological adaptation in biofilm tolerance. J Biol Chem. 2016;291(24):12565-12572. https://doi.org/10.1074/jbc.R115.707257.
  23. Zhao A, Sun J, Liu Y. Understanding bacterial biofilms. Front Cell Infect Microbiol. 2023;13:1137947. https://doi.org/10.3389/fcimb.2023.1137947.
  24. Uruén C, et al. Biofilms as promoters of antibiotic resistance. Antibiotics (Basel). 2020;10(1):3. https://doi.org/10.3390/antibiotics10010003.
  25. Sharma S, et al. Microbial biofilm: formation and control. Microorganisms. 2023;11(6):1614. https://doi.org/10.3390/microorganisms11061614.
  26. Achinas S, Charalampogiannis N, Euverink GJW. Microbial adhesion and biofilms. Appl Sci. 2019;9(14):2801.
  27. Chua SL, et al. Dispersed cells in biofilm transition. Nat Commun. 2014;5:4462. https://doi.org/10.1038/ncomms5462.
  28. Mirghani R, et al. Biofilms: formation and resistance. AIMS Microbiol. 2022;8(3):239-277. https://doi.org/10.3934/microbiol.2022019.
  29. Balcázar JL, Subirats J, Borrego CM. Biofilms as reservoirs of resistance. Front Microbiol. 2015;6:1216. https://doi.org/10.3389/fmicb.2015.01216.
  30. Park S, Sauer K. Cyclic di-GMP signaling in biofilms. Adv Exp Med Biol. 2022;1386:69-94. https://doi.org/10.1007/978-3-031-08491-1_3.
  31. Markowska K, et al. Quorum sensing and biofilm formation. Int J Mol Sci. 2024;25(23):12808.
  32. Azeem K, et al. Biochemistry of bacterial biofilm. Life (Basel). 2025;15(1):49.
  33. Abe K, Nomura N, Suzuki S. Biofilms as HGT hotspots. FEMS Microbiol Ecol. 2020;96(5):fiaa031. https://doi.org/10.1093/femsec/fiaa031.
  34. Ding D, et al. Spread of antibiotic resistance to humans. Ecotoxicol Environ Saf. 2023;254:114734. https://doi.org/10.1016/j.ecoenv.2023.114734.
  35. Almatroudi A. Biofilm resilience in clinical contexts. Biology (Basel). 2025;14(2):165.https://doi.org/10.3390/biology14020165.
  36. Hajiagha MN, Kafil HS. Efflux pumps and biofilm formation. Infect Genet Evol. 2023;112:105459. https://doi.org/10.1016/j.meegid.2023.105459.
  37. Srinivasan R, et al. Biofilm inhibition strategies. Front Microbiol. 2021;12:676458. https://doi.org/10.3389/fmicb.2021.676458.
  38. An AY, et al. Designing anti-biofilm agents. Front Microbiol. 2021;12:640787. https://doi.org/10.3389/fmicb.2021.640787.
  39. Dewan I, Uecker H. Guide to plasmids for modellers. Microbiology (Reading). 2023;169(7):001362. https://doi.org/10.1099/mic.0.001362.
  40. Tao S, et al. Spread of resistance genes in vivo. Can J Infect Dis Med Microbiol. 2022;2022:3348695. https://doi.org/10.1155/2022/3348695.
  41. Derollez E, Lesterlin C, Bigot S. Conjugation-based antibacterial strategies. Microb Biotechnol. 2024;17(11):e70050. https://doi.org/10.1111/1751-7915.70050.
  42. Effe J, et al. Partitioning and toxin-antitoxin systems. Nat Commun. 2025;16:7078. https://doi.org/10.1038/s41467-025-62473-8.
  43. Tsang J. Plasmid addiction systems. Postdoc J. 2017;5(5):3-9.
  44. Garcillán-Barcia MP, de la Cruz F, Rocha EPC. Extended mobility of plasmids. Nucleic Acids Res. 2025;53(14). https://doi.org/10.1093/nar/gkaf652.
  45. Wang X, et al. Inter-plasmid transfer accelerates resistance. ISME J. 2024;18(1). https://doi.org/10.1093/ismejo/wrad032.
  46. Cook LC, Dunny GM. Biofilms in plasmid biology. Microbiol Spectr. 2014;2(5):PLAS-0012-2013. https://doi.org/10.1128/microbiolspec.PLAS-0012-2013.
  47. Mishra A, et al. Medical device-associated biofilm infections. Antibiotics (Basel). 2024;13(7):623. https://doi.org/10.3390/antibiotics13070623.
  48. Pfeifer E, Bonnin RA, Rocha EPC. Phage-plasmids spread resistance. mBio. 2022;13(5):e0185122. https://doi.org/10.1128/mbio.01851-22.
  49. Alav I, Sutton JM, Rahman KM. Efflux pumps in biofilm formation. J Antimicrob Chemother. 2018;73(8):2003-2020. https://doi.org/10.1093/jac/dky042.
  50. Castañeda-Barba S, Top EM, Stalder T. Plasmids in antimicrobial resistance. Nat Rev Microbiol. 2024;22(1):18-32. https://doi.org/10.1038/s41579-023-00926-x.
  51. Vivekanandan KE, et al. Drug resistance and CRISPR solutions. Glob Med Genet. 2025;12(2):100042. https://doi.org/10.1016/j.gmg.2025.100042.
  52. Feng Q, et al. c-di-GMP phosphodiesterase ProE in P. aeruginosa. mSphere. 2025;10(2):e0102624. https://doi.org/10.1128/msphere.01026-24.
  53. Vohra M, et al. Multi-omics insights into P. aeruginosa biofilm. Int J Biol Macromol. 2024;257:128563. https://doi.org/10.1016/j.ijbiomac.2023.128563.
  54. Ramsay KA, et al. Sub-inhibitory antibiotics and mutations. Front Microbiol. 2021;12:789550. https://doi.org/10.3389/fmicb.2021.789550.
  55. Zhao R, et al. SOS response and plasmid conjugation. Microbiol Spectr. 2025;13(7):e0009025. https://doi.org/10.1128/spectrum.00090-25.
  56. Niu H, Gu J, Zhang Y. Bacterial persisters. Signal Transduct Target Ther. 2024;9:174. https://doi.org/10.1038/s41392-024-01866-5.
  57. La Rosa R, Johansen HK, Molin S. Persistent bacterial infections. Antibiotics (Basel). 2022;11(3):419. https://doi.org/10.3390/antibiotics11030419.
  58. Badria FA, et al. Multi-target drug discovery. Front Pharmacol. 2025;16:1633600. https://doi.org/10.3389/fphar.2025.1633600.
  59. Hawas S, Verderosa AD, Totsika M. Combination therapies for biofilms. Front Cell Infect Microbiol. 2022;12:850030. https://doi.org/10.3389/fcimb.2022.850030.
  60. Long D, et al. Ubiquitination mechanisms in lung adenocarcinoma. Int J Mol Sci. 2025;26(13):6501.
  61. Huemer M, et al. Antibiotic resistance and persistence. EMBO Rep. 2020;21(12):e51034. https://doi.org/10.15252/embr.202051034.
  62. Seukep AJ, et al. Thwarting efflux pump-mediated resistance. Antibiotics (Basel). 2022;11(10):1287. https://doi.org/10.3390/antibiotics11101287.
  63. Kumawat M, et al. Efflux pump proteins across species. Microb Pathog. 2023;181:106182. https://doi.org/10.1016/j.micpath.2023.106182.
  64. Shree P, et al. Biofilm structure and resistance. Med Microecol. 2023;16:100084. https://doi.org/10.1016/j.medmic.2023.100084.
  65. Rather MA, Gupta K, Mandal M. Microbial biofilm architecture. Braz J Microbiol. 2021;52(4):1701-1718. https://doi.org/10.1007/s42770-021-00624-x.
  66. Tao S, et al. CRISPR-Cas system in resistance. Infect Drug Resist. 2022;15:4155-4168. https://doi.org/10.2147/IDR.S370869.
  67. Bari AK, et al. Combination drug strategies for biofilm eradication. Front Cell Infect Microbiol. 2023;13:1155699. https://doi.org/10.3389/fcimb.2023.1155699.
  68. Larsson DGJ, Flach CF. Antibiotic resistance in the environment. Nat Rev Microbiol. 2022;20(5):257-269. https://doi.org/10.1038/s41579-021-00649-x.
  69. Li XZ, Plésiat P, Nikaido H. Efflux-mediated resistance in Gram-negative bacteria. Clin Microbiol Rev. 2015;28(2):337-418. https://doi.org/10.1128/CMR.00117-14.
  70. Pai L, et al. Biofilm-induced antimicrobial resistance. Front Cell Infect Microbiol. 2023;13:1327069. https://doi.org/10.3389/fcimb.2023.1327069.
  71. Luo Y, et al. Mechanisms and control of resistance in biofilms. J Microbiol Biotechnol. 2021;31(1):1-7. https://doi.org/10.4014/jmb.2010.10021.
  72. Mobarezi Z, et al. Phage therapy for staphylococcal biofilms. Eur J Med Res. 2025;30:605. https://doi.org/10.1186/s40001-025-02781-3.
  73. Nazir A, et al. Global challenge of antimicrobial resistance. Health Sci Rep. 2025;8(7):e71077. https://doi.org/10.1002/hsr2.71077.