Epigenetic Regulation of Antibiotic Resistance in Bacteria
Epigenetic Regulation of Bacterial Antibiotic Resistance
Abstract
Objective: The objective is to understand how epigenetic mechanisms, such as DNA methylation and nucleoid
associated protein modifications, which regulate gene expression without altering the underlying DNA
sequence, are associated with persistence and antibiotic resistance phenotypes in bacteria, which enable them
to evade host immune responses and resist antimicrobial agents. The study aims to understand how epigenetic
processes that control bacterial gene activity without changing DNA, help bacteria survive antibiotics and
avoid immune system attacks.
Methodology: Peer-reviewed research articles, systematic reviews, and meta-analyses published between
1996 and 2024 were prioritized for inclusion, along with earlier foundational studies where necessary. Global
health reports from organizations such as WHO and CDC were also consulted for epidemiological context.
The keywords, “bacterial epigenetics,” “DNA methylation,” “histone-like protein modification,” “nucleoid
associated proteins,” “RNA regulation,” “epigenetic inheritance,” “antibiotic resistance,” and “antimicrobial
tolerance” were used to search literature.
Results: This review finds that while the well-researched genetic factors are major influencers of bacterial
resistance, genetic factors alone do not fully determine virulence due to the growing number of resistant
strains. Epigenetic mechanisms also contribute by regulating gene expression without introducing permanent
mutations. Rapid bacterial adaptations to antibiotic environments, and the transmission of resistance-associated phenotypes to daughter cells, have been shown to persist in some bacterial species across multiple generations under sustained selective pressure. These findings suggest that incorporating epigenetic targets into existing antimicrobial treatment strategies may improve therapeutic outcomes against resistant bacterial infections. They highlight that this dual-targeting approach may reduce the likelihood of pathogen adaptation, as it simultaneously disrupts multiple resistance-associated mechanisms available for the cell to defend itself. The practical implications of these systems could potentially lead to a decrease in the global recurrence of resistance cases.
Conclusion: Targeting bacterial epigenetic mechanisms, either through inhibitors of methyltransferases and
other regulatory enzyme, or through epigenome editing tools in combination with existing antibiotics, represents a promising way to enhance antibiotic efficacy and reduce the emergence of resistance.
References
Cleveland Clinic. Antibiotic resistance: what is it, complications and treatment [Internet]. 2023 [cited 2026 Jun 26]. Available from: Cleveland Clinic.
World Health Organization. Global antimicrobial resistance and use surveillance system (GLASS) report [Internet]. 2022 [cited 2026 Jun 26]. Available from: World Health Organization.
World Health Organization. Antimicrobial resistance [Internet]. 2023 [cited 2026 Jun 26]. Available from: World Health Organization.
Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiol Spectr. 2016;4(2). doi:10.1128/microbiolspec.VMBF-0016-2015.
Beacham T, Sweet M, Allen M. Large scale cultivation of genetically modified microalgae: a new era for environmental risk assessment. Algal Res. 2017;25:90-100. doi:10.1016/j.algal.2017.04.028.
Amagliani G, Brandi G, Schiavano GF. Incidence and role of Salmonella in seafood safety. Food Res Int. 2012;45(2):780-8. doi:10.1016/j.foodres.2011.06.022.
Ghosh D, Veeraraghavan B, Elangovan R, Perumal V. Antibiotic resistance and epigenetics: more to it than meets the eye. Antimicrob Agents Chemother. 2020;64(2). doi:10.1128/AAC.02225-19.
Motta SS, Cluzel P, Aldana M. Adaptive resistance in bacteria requires epigenetic inheritance, genetic noise, and cost of efflux pumps. PLoS One. 2015;10(3). doi:10.1371/journal.pone.0118464.
Skiada A, Markogiannakis A, Plachouras D, Daikos GL. Adaptive resistance to cationic compounds in Pseudomonas aeruginosa. Int J Antimicrob Agents. 2011;37(3):187-93. doi:10.1016/j.ijantimicag.2010.11.019.
Wang N, Ma T, Yu B. Targeting epigenetic regulators to overcome drug resistance in cancers. Signal Transduct Target Ther. 2023;8:69. doi:10.1038/s41392-023-01341-7.
Batt CA. Genetic modification of bacteria. In: Comprehensive Gut Microbiota. Amsterdam: Elsevier; 2016. p.181-4. doi:10.1016/B978-0-08-100596-5.03022-5.
Okusu H, Ma D, Nikaido H. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants. J Bacteriol. 1996;178(1):306-8. doi:10.1128/jb.178.1.306-308.1996.
Alekshun MN, Levy SB. Alteration of the repressor activity of MarR, the negative regulator of the Escherichia coli marRAB locus, by multiple chemicals in vitro. J Bacteriol. 1999;181(15):4669-72. doi:10.1128/jb.181.15.4669-4672.1999.
Hao Z, Lou H, Zhu R, et al. The multiple antibiotic resistance regulator MarR is a copper sensor in Escherichia coli. Nat Chem Biol. 2014;10(1):21-8. doi:10.1038/nchembio.1380.
Gaurav A, Bakht P, Saini M, et al. Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors. Microbiology. 2023;169(5). doi:10.1099/mic.0.001333.
Soto SM. Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm. Virulence. 2013;4(3):223-9. doi:10.4161/viru.23724.
Corcione S, Longo BM, Scabini S, et al. Risk factors for mortality in Acinetobacter baumannii bloodstream infections and development of a predictive mortality model. J Glob Antimicrob Resist. 2024;38:317-26. doi:10.1016/j.jgar.2024.06.010.
Antunes LCS, Visca P, Towner KJ. Acinetobacter baumannii: evolution of a global pathogen. Pathog Dis. 2014;71(3):292-301. doi:10.1111/2049-632X.12125.
Piperaki ET, Tzouvelekis LS, Miriagou V, Daikos GL. Carbapenem-resistant Acinetobacter baumannii: in pursuit of an effective treatment. Clin Microbiol Infect. 2019;25(8):951-7. doi:10.1016/j.cmi.2019.03.014.
Zack KM, Sorenson T, Joshi SG. Types and mechanisms of efflux pump systems and the potential of efflux pump inhibitors in the restoration of antimicrobial susceptibility, with a special reference to Acinetobacter baumannii. Pathogens. 2024;13(3):197. doi:10.3390/pathogens13030197.
Abdi SN, Ghotaslou R, Ganbarov K, et al. Acinetobacter baumannii efflux pumps and antibiotic resistance. Infect Drug Resist. 2020;13:423-34. doi:10.2147/IDR.S228089.
Gao Q, Lu S, Wang Y, et al. Bacterial DNA methyltransferase: a key to the epigenetic world with lessons learned from proteobacteria. Front Microbiol. 2023;14. doi:10.3389/fmicb.2023.1129437.
Vasu K, Nagaraja V. Diverse functions of restriction-modification systems in addition to cellular defense. Microbiol Mol Biol Rev. 2013;77(1):53-72. doi:10.1128/MMBR.00044-12.
Johnston C, Martin B, Fichant G, et al. Bacterial transformation: distribution, shared mechanisms and divergent control. Nat Rev Microbiol. 2014;12:181-96. doi:10.1038/nrmicro3199.
Jin B, Li Y, Robertson KD. DNA methylation: superior or subordinate in the epigenetic hierarchy? Genes Cancer. 2011;2(6):607-17. doi:10.1177/1947601910393957.
Takahashi K. Influence of bacteria on epigenetic gene control. Cell Mol Life Sci. 2014;71(6):1045-54. doi:10.1007/s00018-013-1487-x.
Delihas N, Forst S. MicF: an antisense RNA gene involved in response of Escherichia coli to global stress factors. J Mol Biol. 2001;313(1):1-12. doi:10.1006/jmbi.2001.5029.
Wang X, Yu D, Chen L. Antimicrobial resistance and mechanisms of epigenetic regulation. Front Cell Infect Microbiol. 2023;13. doi:10.3389/fcimb.2023.1199646.
Jen FE, Scott AL, Tan A, et al. Random switching of the ModA11 type III DNA methyltransferase of Neisseria meningitidis regulates Entner-Doudoroff aldolase expression by a methylation change in the eda promoter region. J Mol Biol. 2020;432(21):5835-42. doi:10.1016/j.jmb.2020.08.024.
Mikucki A, Kahler CM. Microevolution and its impact on hypervirulence, antimicrobial resistance, and vaccine escape in Neisseria meningitidis. Microorganisms. 2023;11(12):3005. doi:10.3390/microorganisms11123005.
Corcoran CP, Dorman CJ. DNA relaxation-dependent phase biasing of the fim genetic switch in Escherichia coli depends on the interplay of H-NS, IHF and LRP. Mol Microbiol. 2009;74(5):1071-82. doi:10.1111/j.1365-2958.2009.06919.x.
Müller CM, Aberg A, Strasevičiene J, et al. Type 1 fimbriae, a colonization factor of uropathogenic Escherichia coli, are controlled by the metabolic sensor CRP-cAMP. PLoS Pathog. 2009;5(2). doi:10.1371/journal.ppat.1000303.
Kuwahara H, Myers CJ, Samoilov MS. Temperature control of fimbriation circuit switch in uropathogenic Escherichia coli: quantitative analysis via automated model abstraction. PLoS Comput Biol. 2010;6(3). doi:10.1371/journal.pcbi.1000723.
Cota I, Sánchez-Romero MA, Hernández SB, et al. Epigenetic control of Salmonella enterica O-antigen chain length: a tradeoff between virulence and bacteriophage resistance. PLoS Genet. 2015;11(11). doi:10.1371/journal.pgen.1005667.
Marshall JM, Gunn JS. The O-antigen capsule of Salmonella enterica serovar Typhimurium facilitates serum resistance and surface expression of FliC. Infect Immun. 2015;83(10):3946-59. doi:10.1128/IAI.00634-15.
Mazgaeen L, Gurung P. Recent advances in lipopolysaccharide recognition systems. Int J Mol Sci. 2020;21(2):379. doi:10.3390/ijms21020379.
Ackermann M. A functional perspective on phenotypic heterogeneity in microorganisms. Nat Rev Microbiol. 2015;13:497-508. doi:10.1038/nrmicro3491.
Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2007;5:48-56. doi:10.1038/nrmicro1557.
Fisher RA, Gollan B, Helaine S. Persistent bacterial infections and persister cells. Nat Rev Microbiol. 2017;15:453-64. doi:10.1038/nrmicro.2017.42.
Windels EM, Michiels JE, Fauvart M, et al. Bacterial persistence promotes the evolution of antibiotic resistance by increasing survival and mutation rates. ISME J. 2019;13(5):1239-51. doi:10.1038/s41396-019-0344-9.
Vogwill T, Comfort AC, Furió V, MacLean RC. Persistence and resistance as complementary bacterial adaptations to antibiotics. J Evol Biol. 2016;29(6):1223-33. doi:10.1111/jeb.12864.
Remesh SG, Verma SC, Chen JH, et al. Nucleoid remodeling during environmental adaptation is regulated by HU-dependent DNA bundling. Nat Commun. 2020;11(1):2905. doi:10.1038/s41467-020-16724-5.
Centers for Disease Control and Prevention. How antimicrobial resistance spreads [Internet]. 2024 [cited 2026 Jun 26]. Available from: CDC.
NYU Langone Health. Medication for antibiotic resistant infection [Internet]. [cited 2026 Jun 26]. Available from: NYU Langone Health.
Farani MR, Sarlak M, Gholami A, et al. Epigenetic drugs as new emerging therapeutics: what is the scale's orientation of application and challenges? Pathol Res Pract. 2023;248:154688. doi:10.1016/j.prp.2023.154688.
Heerboth S, Lapinska K, Snyder N, et al. Use of epigenetic drugs in disease: an overview. Epigenetics Insights. 2014;6:9-19. doi:10.4137/GEG.S12270.
Grosso R, Nguyen V, Ahmed SK, Wong-Beringer A. Novel epigallocatechin gallate (EGCG) analogs with improved biochemical properties for targeting extracellular and intracellular Staphylococcus aureus. Appl Microbiol. 2024;4(4):1568-81. doi:10.3390/applmicrobiol4040107.
BiteSizeBio. Dead useful: CRISPR-Cas9 epigenome editing [Internet]. 2024 [cited 2026 Jun 26]. Available from: BiteSizeBio.
Balcha FB, Neja SA. CRISPR-Cas9 mediated phage therapy as an alternative to antibiotics. Anim Dis. 2023;3:4. doi:10.1186/s44149-023-00065-z.
Copyright (c) 2026 Annals of Jinnah Sindh Medical University
This work is licensed under a Creative Commons Attribution 4.0 International License.
