Bacteriophages: Potential Candidates for the Dissemination of Antibiotic Resistance Genes in the Environment
Abstract
1. Introduction
2. Bacteriophages: Abundance in the Environment
3. Bacteriophages: A Vehicle for Resistance Genes
4. Antibiotic Resistance Genes’ Transmission Mechanisms
4.1. Conjugation
4.2. Transformation
4.3. Transduction
5. Resistance Genes’ Transmission Mechanisms in Bacteriophages
6. Phage Dissemination of ARGs via Transduction
7. Bacterial Genes and ARGs in Viral Communities
8. ARG Transfer by Bacteriophages
9. Clinical Implications and Safety-by-Design Principles
10. Conclusions/Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ARG | Antibiotic resistance genes |
HGT | Horizontal gene transfer |
ICEs | Integration and conjugation elements |
MGEs | Mobile genetic elements |
MDR | Multidrug resisatnce |
WHO | World Health Organization |
CDC | Center For Disease Control |
VBR | Virus-to-bacterium |
VLPs | Virus-like particles |
WGS | Whole-genome sequencing |
References
- Kapoor, G.; Saigal, S.; Elongavan, A. Action and resistance mechanisms of antibiotics: A guide for clinicians. J. Anaesthesiol. Clin. Pharmacol. 2017, 33, 300–305. [Google Scholar] [CrossRef] [PubMed]
- Murray, C.J.; Ikuta, K.S.; Sharara, F.; Swetschinski, L.; Aguilar, G.R.; Gray, A.; Han, C.; Bisignano, C.; Rao, P.; Wool, E. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet 2022, 399, 629–655. [Google Scholar] [CrossRef] [PubMed]
- Sher, S.; Richards, G.P.; Parveen, S.; Williams, H.N. Characterization of Antibiotic Resistance in Shewanella Species: An Emerging Pathogen in Clinical and Environmental Settings. Microorganisms 2025, 13, 1115. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Z.; Zhang, Q.; Wang, T.; Xu, N.; Lu, T.; Hong, W.; Penuelas, J.; Gillings, M.; Wang, M.; Gao, W. Assessment of global health risk of antibiotic resistance genes. Nat. Commun. 2022, 13, 1553. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Guo, Y.; Qiu, T.; Gao, M.; Wang, X. Bacteriophages: Underestimated vehicles of antibiotic resistance genes in the soil. Front. Microbiol. 2022, 13, 936267. [Google Scholar] [CrossRef] [PubMed]
- Munita, J.M.; Arias, C.A. Mechanisms of antibiotic resistance. Microbiol. Spectr. 2016, 4, 481–511. [Google Scholar] [CrossRef] [PubMed]
- Stokes, H.W.; Gillings, M.R. Gene flow, mobile genetic elements and the recruitment of antibiotic resistance genes into Gram-negative pathogens. FEMS Microbiol. Rev. 2011, 35, 790–819. [Google Scholar] [CrossRef] [PubMed]
- Linares, R.; Breyton, C. About bacteriophage tail terminator and tail completion proteins: Structure of the proximal extremity of siphophage T5 tail. J. Virol. 2025, 99, e01376. [Google Scholar] [CrossRef] [PubMed]
- Coshic, K.; Maffeo, C.; Winogradoff, D.; Aksimentiev, A.J.N. The structure and physical properties of a packaged bacteriophage particle. Nature 2024, 627, 905–914. [Google Scholar] [CrossRef] [PubMed]
- Puxty, R.J.; Millard, A.D. Functional ecology of bacteriophages in the environment. Curr. Opin. Microbiol. 2023, 71, 102245. [Google Scholar] [CrossRef] [PubMed]
- Batinovic, S.; Wassef, F.; Knowler, S.A.; Rice, D.T.; Stanton, C.R.; Rose, J.; Tucci, J.; Nittami, T.; Vinh, A.; Drummond, G.R. Bacteriophages in natural and artificial environments. Pathogens 2019, 8, 100. [Google Scholar] [CrossRef] [PubMed]
- Glasner, M.E. Finding enzymes in the gut metagenome. Science 2017, 355, 577–578. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, S.; Baker, K.; Padman, B.S.; Patwa, R.; Dunstan, R.A.; Weston, T.A.; Schlosser, K.; Bailey, B.; Lithgow, T.; Lazarou, M. Bacteriophage transcytosis provides a mechanism to cross epithelial cell layers. MBio 2017, 8, e01874-17. [Google Scholar] [CrossRef] [PubMed]
- Naureen, Z.; Dautaj, A.; Anpilogov, K.; Camilleri, G.; Dhuli, K.; Tanzi, B.; Maltese, P.E.; Cristofoli, F.; De Antoni, L.; Beccari, T. Bacteriophages presence in nature and their role in the natural selection of bacterial populations. Acta Bio Medica Atenei Parm. 2020, 91 (Suppl. 13), e2020024. [Google Scholar]
- Florent, P.; Cauchie, H.-M.; Herold, M.; Jacquet, S.; Ogorzaly, L. Soil ph, calcium content and bacteria as major factors responsible for the distribution of the known fraction of the DNA bacteriophage populations in soils of Luxembourg. Microorganisms 2022, 10, 1458. [Google Scholar] [CrossRef] [PubMed]
- Simmonds, P.; Aiewsakun, P. Virus classification–where do you draw the line? Arch. Virol. 2018, 163, 2037–2046. [Google Scholar] [CrossRef] [PubMed]
- Balcazar, J.L. Bacteriophages as vehicles for antibiotic resistance genes in the environment. PLoS Pathog. 2014, 10, e1004219. [Google Scholar] [CrossRef] [PubMed]
- Sher, S.; Sultan, S.; Rehman, A. Characterization of multiple metal resistant Bacillus licheniformis and its potential use in arsenic contaminated industrial wastewater. Appl. Water Sci. 2021, 11, 1–7. [Google Scholar] [CrossRef]
- Partridge, S.R.; Kwong, S.M.; Firth, N.; Jensen, S.O. Mobile genetic elements associated with antimicrobial resistance. Clin. Microbiol. Rev. 2018, 31, e00088-17. [Google Scholar] [CrossRef] [PubMed]
- Li, B.; Qiu, Y.; Song, Y.; Lin, H.; Yin, H. Dissecting horizontal and vertical gene transfer of antibiotic resistance plasmid in bacterial community using microfluidics. Environ. Int. 2019, 131, 105007. [Google Scholar] [CrossRef] [PubMed]
- Tao, S.; Chen, H.; Li, N.; Wang, T.; Liang, W. The spread of antibiotic resistance genes in vivo model. Can. J. Infect. Dis. Med. Microbiol. 2022, 2022, 3348695. [Google Scholar] [CrossRef] [PubMed]
- Lopatkin, A.J.; Sysoeva, T.A.; You, L. Dissecting the effects of antibiotics on horizontal gene transfer: Analysis suggests a critical role of selection dynamics. Bioessays 2016, 38, 1283–1292. [Google Scholar] [CrossRef] [PubMed]
- Wang, R.; Liu, Y.; Zhang, Q.; Jin, L.; Wang, Q.; Zhang, Y.; Wang, X.; Hu, M.; Li, L.; Qi, J. The prevalence of colistin resistance in Escherichia coli and Klebsiella pneumoniae isolated from food animals in China: Coexistence of mcr-1 and blaNDM with low fitness cost. Int. J. Antimicrob. Agents 2018, 51, 739–744. [Google Scholar] [CrossRef] [PubMed]
- Evans, B.A.; Kumar, A.; Castillo-Ramírez, S. Genomic basis of antibiotic resistance and virulence in Acinetobacter. Front. Microbiol. 2021, 12, 690. [Google Scholar] [CrossRef] [PubMed]
- Yu, Z.; Wang, Y.; Henderson, I.R.; Guo, J. Artificial sweeteners stimulate horizontal transfer of extracellular antibiotic resistance genes through natural transformation. ISME J. 2022, 16, 543–554. [Google Scholar] [CrossRef] [PubMed]
- Winter, M.; Buckling, A.; Harms, K.; Johnsen, P.J.; Vos, M. Antimicrobial resistance acquisition via natural transformation: Context is everything. Curr. Opin. Microbiol. 2021, 64, 133–138. [Google Scholar] [CrossRef] [PubMed]
- Voigt, E.; Rall, B.C.; Chatzinotas, A.; Brose, U.; Rosenbaum, B. Phage strategies facilitate bacterial coexistence under environmental variability. PeerJ 2021, 9, e12194. [Google Scholar] [CrossRef] [PubMed]
- Haaber, J.; Penadés, J.R.; Ingmer, H. Transfer of antibiotic resistance in Staphylococcus aureus. Trends Microbiol. 2017, 25, 893–905. [Google Scholar] [CrossRef] [PubMed]
- Kasman, L.; Porter, L. Bacteriophages. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
- Schneider, C.L. Bacteriophage-Mediated Horizontal Gene Transfer: Transduction. In Bacteriophages: Biology, Technology, Therapy; Springer: Cham, Switzerland, 2021; pp. 151–192. [Google Scholar]
- Wood, S.J.; Kuzel, T.M.; Shafikhani, S.H. Pseudomonas aeruginosa: Infections, animal modeling, and therapeutics. Cells 2023, 12, 199. [Google Scholar] [CrossRef] [PubMed]
- Fišarová, L.; Botka, T.; Du, X.; Mašlaňová, I.; Bárdy, P.; Pantůček, R.; Benešík, M.; Roudnický, P.; Winstel, V.; Larsen, J. Staphylococcus epidermidis phages transduce antimicrobial resistance plasmids and mobilize chromosomal islands. Msphere 2021, 6, 10–128. [Google Scholar] [CrossRef] [PubMed]
- Frosini, S.M.; Bond, R.; McCarthy, A.J.; Feudi, C.; Schwarz, S.; Lindsay, J.A.; Loeffler, A. Genes on the move: In vitro transduction of antimicrobial resistance genes between human and canine staphylococcal pathogens. Microorganisms 2020, 8, 2031. [Google Scholar] [CrossRef] [PubMed]
- Hussain, H.I.; Aqib, A.I.; Seleem, M.N.; Shabbir, M.A.; Hao, H.; Iqbal, Z.; Kulyar, M.F.-e.-A.; Zaheer, T.; Li, K. Genetic basis of molecular mechanisms in β-lactam resistant gram-negative bacteria. Microb. Pathog. 2021, 158, 105040. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; He, X.; Shen, S.; Shi, M.; Zhou, Q.; Liu, J.; Wang, M.; Sun, Y. Effects of the newly isolated T4-like phage on transmission of plasmid-borne antibiotic resistance genes via generalized transduction. Viruses 2021, 13, 2070. [Google Scholar] [CrossRef] [PubMed]
- Zeman, M.; Mašlaňová, I.; Indráková, A.; Šiborová, M.; Mikulášek, K.; Bendíčková, K.; Plevka, P.; Vrbovská, V.; Zdráhal, Z.; Doškař, J. Staphylococcus sciuri bacteriophages double-convert for staphylokinase and phospholipase, mediate interspecies plasmid transduction, and package mecA gene. Sci. Rep. 2017, 7, 46319. [Google Scholar] [CrossRef] [PubMed]
- Chen, J.; Quiles-Puchalt, N.; Chiang, Y.N.; Bacigalupe, R.; Fillol-Salom, A.; Chee, M.S.J.; Fitzgerald, J.R.; Penadés, J.R. Genome hypermobility by lateral transduction. Science 2018, 362, 207–212. [Google Scholar] [CrossRef] [PubMed]
- Humphrey, S.; Fillol-Salom, A.; Quiles-Puchalt, N.; Ibarra-Chávez, R.; Haag, A.F.; Chen, J.; Penadés, J.R. Bacterial chromosomal mobility via lateral transduction exceeds that of classical mobile genetic elements. Nat. Commun. 2021, 12, 6509. [Google Scholar] [CrossRef] [PubMed]
- Chen, Q.; Dharmaraj, T.; Cai, P.C.; Burgener, E.B.; Haddock, N.L.; Spakowitz, A.J.; Bollyky, P.L. Bacteriophage and bacterial susceptibility, resistance, and tolerance to antibiotics. Pharmaceutics 2022, 14, 1425. [Google Scholar] [CrossRef] [PubMed]
- Goh, S.; Hussain, H.; Chang, B.J.; Emmett, W.; Riley, T.V.; Mullany, P. Phage ϕC2 mediates transduction of Tn 6215, encoding erythromycin resistance, between Clostridium difficile strains. MBio 2013, 4, 10.1128-13. [Google Scholar] [CrossRef] [PubMed]
- Mazaheri Nezhad Fard, R.; Barton, M.D.; Heuzenroeder, M.W. Bacteriophage-mediated transduction of antibiotic resistance in enterococci. Lett. Appl. Microbiol. 2011, 52, 559–564. [Google Scholar] [CrossRef] [PubMed]
- Lee, Y.D.; Park, J.H. Phage conversion for β-lactam antibiotic resistance of Staphylococcus aureus from foods. J. Microbiol. Biotechnol. 2016, 26, 263–269. [Google Scholar] [CrossRef] [PubMed]
- Varga, M.; Kuntová, L.; Pantůček, R.; Mašlaňová, I.; Růžičková, V.; Doškař, J.J.F.m.l. Efficient transfer of antibiotic resistance plasmids by transduction within methicillin-resistant Staphylococcus aureus USA300 clone. FEMS Microbiol. Lett. 2012, 332, 146–152. [Google Scholar] [CrossRef] [PubMed]
- Sun, R.; Yu, P.; Zuo, P.; Alvarez, P.J. Bacterial concentrations and water turbulence influence the importance of conjugation versus phage-mediated antibiotic resistance gene transfer in suspended growth systems. ACS Environ. Au 2021, 2, 156–165. [Google Scholar] [CrossRef] [PubMed]
- Mutuku, C.; Gazdag, Z.; Melegh, S. Occurrence of antibiotics and bacterial resistance genes in wastewater: Resistance mechanisms and antimicrobial resistance control approaches. World J. Microbiol. Biotechnol. 2022, 38, 152. [Google Scholar] [CrossRef] [PubMed]
- Pailhoriès, H.; Herrmann, J.-L.; Velo-Suarez, L.; Lamoureux, C.; Beauruelle, C.; Burgel, P.-R.; Héry-Arnaud, G. Antibiotic resistance in chronic respiratory diseases: From susceptibility testing to the resistome. Eur. Respir. Rev. 2022, 31, 210259. [Google Scholar] [CrossRef] [PubMed]
- Debroas, D.; Siguret, C. Viruses as key reservoirs of antibiotic resistance genes in the environment. ISME J. 2019, 13, 2856–2867. [Google Scholar] [CrossRef] [PubMed]
- Rodríguez-Rubio, L.; Haarmann, N.; Schwidder, M.; Muniesa, M.; Schmidt, H. Bacteriophages of Shiga toxin-producing Escherichia coli and their contribution to pathogenicity. Pathogens 2021, 10, 404. [Google Scholar] [CrossRef] [PubMed]
- Ballesté, E.; Blanch, A.R.; Muniesa, M.; García-Aljaro, C.; Rodríguez-Rubio, L.; Martín-Díaz, J.; Pascual-Benito, M.; Jofre, J. Bacteriophages in sewage: Abundance, roles, and applications. FEMS Microbes 2022, 3, xtac009. [Google Scholar] [CrossRef] [PubMed]
- McShan, W.M.; Nguyen, S.V. The Bacteriophages of Streptococcus Pyogenes. In Streptococcus Pyogenes: Basic Biology to Clinical Manifestations [Internet]; University of Oklahoma Health Sciences Cente: Oklahoma, OK, USA, 2016. [Google Scholar]
- Giovanetti, E.; Brenciani, A.; Vecchi, M.; Manzin, A.; Varaldo, P.E. Prophage association of mef (A) elements encoding efflux-mediated erythromycin resistance in Streptococcus pyogenes. J. Antimicrob. Chemother. 2005, 55, 445–451. [Google Scholar] [CrossRef] [PubMed]
- Colomer-Lluch, M.; Jofre, J.; Muniesa, M. Antibiotic resistance genes in environmental bacteriophages DNA fraction of environmental samples. PLoS ONE 2011, 6, e17549. [Google Scholar] [CrossRef] [PubMed]
- MacNair, C.R.; Rutherford, S.T.; Tan, M.-W.J.N.R.M. Alternative therapeutic strategies to treat antibiotic-resistant pathogens. Nat. Rev. Microbiol. 2024, 22, 262–275. [Google Scholar] [CrossRef] [PubMed]
- Pattnaik, A.; Pati, S.; Samal, S.K. Bacteriophage as a potential biotherapeutics to combat present-day crisis of multi-drug resistant pathogens. Heliyon 2024, 10, e37489. [Google Scholar] [CrossRef] [PubMed]
- Rózsa, Á.; Orosz, L.; Szemerédi, N.; Spengler, G.; Kecskeméti, G.; Vágó, O.; Sárvári, K.P.; Szabó, D.; Szabó, Z.; Burián, K.J.A. Bacteriophage Treatment Induces Phenotype Switching and Alters Antibiotic Resistance of ESBL Escherichia coli. Antibiotics 2025, 14, 76. [Google Scholar] [CrossRef] [PubMed]
- Chaudhary, N.; Sharma, K.; Kaur, H.; Prajapati, S.; Mohan, B.; Taneja, N. CRISPR-Cas-assisted phage engineering for personalized antibacterial treatments. Indian J. Med. Microbiol. 2025, 53, 100771. [Google Scholar] [CrossRef] [PubMed]
Source Bacteria | Phage | Transferred ARGs | Recipient Bacteria | Transduction Frequency (Transductants/Pfu) | References |
---|---|---|---|---|---|
Clostridium difficile CD38 | ϕC2 | ermB | Clostridium difficile CD062 | 10−6 | [40] |
Enterococcus Gallinarum Enterococcus faecalis | EGRM195 EFRM31 | tetL aac6-aph2 | Enterococcus faecalis Enterococcus faecium | 10−8–10−9 (tet) 10−7–10−9 (gent) | [41] |
Staphylococcus aureus S123 | TEM123 | NDM-1 | Staphylococcus aureus S133 | 10−1 | [42] |
Streptococcus pyogenes 07/759 | Φ 80a | blaZ, cadD | Streptococcus pyogenes 07/235 | 1.5 × 10−5 | [43] |
E. coli DH5α | λ phage | genR | E. coli MG1655 | 10−6 | [44] |
Antibiotic | Genes (Resistance) | Natural Source |
---|---|---|
Bacitracin | bcrA | Viromes of the human gut, microbiomes in fecal of swine, sputum microbiota of cystic fibrosis |
B-lactams antibiotics | blaOXA-2 blaPSE-1, blaPSE-4, blaPSE-type genes | Sewage |
B-lactams antibiotics | blaTEM, blaCTX-M | Water from sewage, river, and animal waste |
B-lactams antibiotics | blaCTX-M-10 | Enterobacteriaceae |
Ampicillin | blaCMY-2 | Salmonella enterica |
Trimethoprim | dfrAa | Microbiomes of Swine fecal |
Fluoroquinolones | Fluoroquinolone resistance genes | Sputum microbiota of cystic fibrosis |
Macrolides | macB | Microbiomes in fecal of swine |
Methicillin | mecA | Water from sewage, river, and animal waste |
Macrolides | mefA | Streptococcus pyogenes |
Tetracycline | tetW | Viromes of human gut, microbiomes in the feces of swine |
Tetracycline | Tet37 | Microbiomes in fecal of swine |
Tetracycline | tetA, tetB | S. enterica |
Vancomycin | Vancomycin resistance genes | Viromes of the human gut, microbiomes in the feces of swine |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Sher, S.; Khan, H.A.; Khan, Z.; Siddique, M.S.; Bukhari, D.A.; Rehman, A. Bacteriophages: Potential Candidates for the Dissemination of Antibiotic Resistance Genes in the Environment. Targets 2025, 3, 25. https://doi.org/10.3390/targets3030025
Sher S, Khan HA, Khan Z, Siddique MS, Bukhari DA, Rehman A. Bacteriophages: Potential Candidates for the Dissemination of Antibiotic Resistance Genes in the Environment. Targets. 2025; 3(3):25. https://doi.org/10.3390/targets3030025
Chicago/Turabian StyleSher, Shahid, Husnain Ahmad Khan, Zaman Khan, Muhammad Sohail Siddique, Dilara Abbas Bukhari, and Abdul Rehman. 2025. "Bacteriophages: Potential Candidates for the Dissemination of Antibiotic Resistance Genes in the Environment" Targets 3, no. 3: 25. https://doi.org/10.3390/targets3030025
APA StyleSher, S., Khan, H. A., Khan, Z., Siddique, M. S., Bukhari, D. A., & Rehman, A. (2025). Bacteriophages: Potential Candidates for the Dissemination of Antibiotic Resistance Genes in the Environment. Targets, 3(3), 25. https://doi.org/10.3390/targets3030025