Abstract
Antimicrobial-resistant bacteria have become a global concern, necessitating the development of novel antimicrobial agents. Bacteriocins, antimicrobial peptides produced by bacteria, are promising candidates. In this study, we screened Staphylococcus capitis isolates to identify bacteriocins effective against methicillin-resistant Staphylococcus aureus (MRSA). We discovered that one strain, HBC3, exhibited strong activity against Gram-positive bacteria, including MRSA. Genome analysis revealed a unique plasmid encoding two bacteriocin synthesis genes: capidermicin, a class II bacteriocin, and micrococcin P1 (MP1), a thiopeptide. MP1 was first identified in S. capitis. Loss of the plasmid abolished the antibacterial activity. We purified both peptides and evaluated their spectrum of activity. MP1 showed broad activity, especially against Gram-positive cocci, whereas capidermicin was active mainly against Gram-positive rods. These findings demonstrate that S. capitis HBC3 harbors a plasmid encoding two distinct bacteriocins with complementary antibacterial spectra, highlighting the cooperative potential of bacteriocins in combating resistant bacteria.
Data availability
The complete genome of *S. capitis* HBC3 has been deposited in the National Center for Biotechnology Information (NCBI) database under accession number SRR33407742 (Bioproject: PRJNA1258066).
Materials availability
This study did not generate new unique reagents.
Abbreviations
- MRSA:
-
Methicillin-resistant Staphylococcus aureus
- VRE:
-
Vancomycin-resistant enterococci
- MP1:
-
Micrococcin P1
- HPLC:
-
High-performance liquid chromatography
- ESI-MS:
-
Electrospray ionization mass spectrometry
References
GBD 2021 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. Lancet 404, 1199–1226 (2024).
Karaman, R., Jubeh, B. & Breijyeh, Z. Resistance of Gram-Positive bacteria to current antibacterial agents and overcoming approaches. Molecules 25, (2020).
Sousa, S. A. et al. Bacterial nosocomial infections: multidrug resistance as a trigger for the development of novel antimicrobials. Antibiotics (Basel) 10, (2021).
Wong, J. W. et al. Prevalence and risk factors of community-associated methicillin-resistant Staphylococcus aureus carriage in Asia-Pacific region from 2000 to 2016: a systematic review and meta-analysis. Clin. Epidemiol. 10, 1489–1501 (2018).
Nakaminami, H. Molecular epidemiological features of Methicillin-Resistant Staphylococcus aureus in Japan. Biol. Pharm. Bull. 48, 196–204 (2025).
Tsiodras, S. et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 358, 207–208 (2001).
Munita, J. M., Bayer, A. S. & Arias, C. A. Evolving resistance among Gram-positive pathogens. Clin. Infect. Dis. 61 (Suppl 2), S48–57 (2015).
Harada, Y. et al. Nosocomial spread of meticillin-resistant Staphylococcus aureus with β-lactam-inducible Arbekacin resistance. J. Med. Microbiol. 63, 710–714 (2014).
Shariati, A. et al. Global prevalence and distribution of Vancomycin resistant, Vancomycin intermediate and heterogeneously Vancomycin intermediate Staphylococcus aureus clinical isolates: a systematic review and meta-analysis. Sci. Rep. 10, 12689 (2020).
Wu, Q. et al. Systematic review and meta-analysis of the epidemiology of vancomycin-resistance Staphylococcus aureus isolates. Antimicrob. Resist. Infect. Control. 10, 101 (2021).
Faron, M. L., Ledeboer, N. A. & Buchan, B. W. Resistance Mechanisms, Epidemiology, and approaches to screening for Vancomycin-Resistant Enterococcus in the health care setting. J. Clin. Microbiol. 54, 2436–2447 (2016).
Cotter, P. D., Hill, C. & Ross, R. P. Bacteriocins: developing innate immunity for food. Nat. Rev. Microbiol. 3, 777–788 (2005).
Jack, R. W., Tagg, J. R. & Ray, B. Bacteriocins of gram-positive bacteria. Microbiol. Rev. 59, 171–200 (1995).
Nisar, S., Shah, A. H. & Nazir, R. The clinical praxis of bacteriocins as natural anti-microbial therapeutics. Arch. Microbiol. 206, 451 (2024).
Bastos, M. C. F., Ceotto, H., Coelho, M. L. V. & Nascimento, J. S. Staphylococcal antimicrobial peptides: relevant properties and potential biotechnological applications. Curr. Pharm. Biotechnol. 10, 38–61 (2009).
Suzuki, Y. et al. The two-component regulatory systems GraRS and SrrAB mediate Staphylococcus aureus susceptibility to Pep5 produced by clinical isolate of Staphylococcus epidermidis. Appl. Environ. Microbiol. 90, e0030024 (2024).
Nakazono, K. et al. Complete sequences of epidermin and Nukacin encoding plasmids from oral-derived Staphylococcus epidermidis and their antibacterial activity. PLoS One. 17, e0258283 (2022).
Kumar, R., Jangir, P. K., Das, J., Taneja, B. & Sharma, R. Genome analysis of Staphylococcus capitis TE8 reveals repertoire of antimicrobial peptides and adaptation strategies for growth on human skin. Sci. Rep. 7, 10447 (2017).
O’Sullivan, J. N. et al. Nisin J, a novel natural Nisin Variant, is produced by Staphylococcus capitis sourced from the human skin microbiota. J Bacteriol 202, (2020).
Lynch, D. et al. Identification and characterisation of capidermicin, a novel bacteriocin produced by Staphylococcus capitis. PLoS One. 14, e0223541 (2019).
Fernández-Fernández, R. et al. Genomic analysis of Bacteriocin-Producing staphylococci: high prevalence of lanthipeptides and the micrococcin P1 biosynthetic gene clusters. Probiotics Antimicrob. Proteins. 17, 159–174 (2025).
Liu, Y. et al. Skin microbiota analysis-inspired development of novel anti-infectives. Microbiome 8, 85 (2020).
Wan, Y. et al. Complete genome assemblies and antibiograms of 22 Staphylococcus capitis isolates. BMC Genom Data. 26, 12 (2025).
Fernández-Fernández, R. et al. Detection and evaluation of the antimicrobial activity of micrococcin P1 isolated from commensal and environmental Staphylococcal isolates against MRSA. Int. J. Antimicrob. Agents. 62, 106965 (2023).
de Freire Bastos, M. C., Miceli de Farias, F., Carlin Fagundes, P. & Varella Coelho, M. L. Staphylococcins: an update on antimicrobial peptides produced by Staphylococci and their diverse potential applications. Appl. Microbiol. Biotechnol. 104, 10339–10368 (2020).
Ovchinnikov, K. V. et al. A strong synergy between the thiopeptide bacteriocin micrococcin P1 and rifampicin against MRSA in a murine skin infection model. Front. Immunol. 12, 676534 (2021).
Ongpipattanakul, C. et al. Mechanism of action of ribosomally synthesized and Post-Translationally modified peptides. Chem. Rev. 122, 14722–14814 (2022).
Ciufolini, M. A. & Lefranc, D. Micrococcin P1: structure, biology and synthesis. Nat. Prod. Rep. 27, 330–342 (2010).
Liu, Y. et al. Essential role of membrane vesicles for biological activity of the bacteriocin micrococcin P1. J. Extracell. Vesicles. 11, e12212 (2022).
Reifsteck, F., Wee, S. & Wilkinson, B. J. Hydrophobicity-hydrophilicity of Staphylococci. J. Med. Microbiol. 24, 65–73 (1987).
Rawlinson, L. A. B., O’Gara, J. P., Jones, D. S. & Brayden, D. J. Resistance of Staphylococcus aureus to the cationic antimicrobial agent poly(2-(dimethylamino ethyl)methacrylate) (pDMAEMA) is influenced by cell-surface charge and hydrophobicity. J. Med. Microbiol. 60, 968–976 (2011).
Li, M. et al. Lethal hydroxyl radical accumulation by a lactococcal bacteriocin, lacticin Q. Antimicrob. Agents Chemother. 57, 3897–3902 (2013).
Netz, D. J. A., Bastos, M. do C. de F. & Sahl, H.-G. Mode of action of the antimicrobial peptide Aureocin A53 from Staphylococcus aureus. Appl. Environ. Microbiol. 68, 5274–5280 (2002).
Lynch, D., Hill, C., Field, D. & Begley, M. Inhibition of Listeria monocytogenes by the Staphylococcus capitis - derived bacteriocin capidermicin. Food Microbiol. 94, 103661 (2021).
Brdová, D., Ruml, T. & Viktorová, J. Mechanism of Staphylococcal resistance to clinically relevant antibiotics. Drug Resist. Updat. 77, 101147 (2024).
Nam, E. Y. et al. Emergence of Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus clinical isolates among Daptomycin-Naive patients in Korea. Microb. Drug Resist. 24, 534–541 (2018).
Ernst, C. M. & Peschel, A. MprF-mediated daptomycin resistance. Int. J. Med. Microbiol. 309, 359–363 (2019).
Siguier, P., Gourbeyre, E. & Chandler, M. Bacterial insertion sequences: their genomic impact and diversity. FEMS Microbiol. Rev. 38, 865–891 (2014).
Varani, A., He, S., Siguier, P., Ross, K. & Chandler, M. The IS6 family, a clinically important group of insertion sequences including IS26. Mob. DNA. 12, 11 (2021).
Partridge, S. R., Kwong, S. M., Firth, N. & Jensen, S. O. Mobile genetic elements associated with antimicrobial resistance. Clin Microbiol. Rev 31, (2018).
Memariani, H., Memariani, M., Eskandari, S. E. & Ghasemian, A. Nour Neamatollahi, A. The potential role of probiotics and their bioactive compounds in the management of pulmonary tuberculosis. J. Infect. Public. Health. 18, 102840 (2025).
Roy, S. & Dhaneshwar, S. Role of prebiotics, probiotics, and synbiotics in management of inflammatory bowel disease: current perspectives. World J. Gastroenterol. 29, 2078–2100 (2023).
Kommineni, S. et al. Bacteriocin production augments niche competition by enterococci in the mammalian Gastrointestinal tract. Nature 526, 719–722 (2015).
Laurent, F. & Butin, M. Staphylococcus capitis and NRCS-A clone: the story of an unrecognized pathogen in neonatal intensive care units. Clin. Microbiol. Infect. 25, 1081–1085 (2019).
Cotter, P. D., Ross, R. P. & Hill, C. Bacteriocins - a viable alternative to antibiotics? Nat. Rev. Microbiol. 11, 95–105 (2013).
Kusaka, S. et al. Oral and rectal colonization of methicillin-resistant Staphylococcus aureus in long-term care facility residents and their association with clinical status. Microbiol. Immunol. 68, 75–89 (2024).
Kawayanagi, T. et al. The oral cavity is a potential reservoir of gram-negative antimicrobial-resistant bacteria, which are correlated with ageing and the number of teeth. Heliyon 10, e39827 (2024).
Wick, R. R., Judd, L. M., Gorrie, C. L. & Holt, K. E. Unicycler: resolving bacterial genome assemblies from short and long sequencing reads. PLoS Comput. Biol. 13, e1005595 (2017).
van Heel, A. J. et al. BAGEL4: a user-friendly web server to thoroughly mine RiPPs and bacteriocins. Nucleic Acids Res. 46, W278–W281 (2018).
Blin, K. et al. AntiSMASH 7.0: new and improved predictions for detection, regulation, chemical structures and visualisation. Nucleic Acids Res. 51, W46–W50 (2023).
Alikhan, N. F., Petty, N. K., Zakour, B., Beatson, S. A. & N. L. & BLAST ring image generator (BRIG): simple prokaryote genome comparisons. BMC Genom. 12, 402 (2011).
Sullivan, M. J., Petty, N. K. & Beatson, S. A. Easyfig: a genome comparison visualizer. Bioinformatics 27, 1009–1010 (2011).
Ersfeld-Dressen, H., Sahl, H. G. & Brandis, H. Plasmid involvement in production of and immunity to the staphylococcin-like peptide Pep 5. J. Gen. Microbiol. 130, 3029–3035 (1984).
Acknowledgements
Conceptualization: Data curation: Formal analysis: Funding acquisition: Investigation: Methodology: Project Administration: Resources: Software: Supervision: Validation: Visualization: Writing-original draft: Writing-review and editing: We declare that there are no conflicts of interest.We thank Dr. Tomoko Amimoto, the Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University for the measurement of ESI-MS analysis.
Funding
This study was supported in part by a Grant-in-Aid for Scientific Research (C) (Grant No. 21K12886) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP23fk0108606 and JP25fk0108699.
Author information
Authors and Affiliations
Contributions
Conceptualization: Yu.S., M.K.-M. and H.K. Data curation: K.O., Yu.S. and H.K. Formal analysis: K.O. and Yu.S. Funding acquisition: M.K.-M., M.S. and H.K. Investigation: K.O., Yu.S., T.H., M.N.-T.L., J.H., Yo. S., and H.K. Methodology: Yu.S., M.K.-M., and H.K. Project Administration: M.K.-M., T.A. and H.K. Resources: M.K.-M., J.H., M.S. and H.K. Software: Yu.S., M.K.-M. and M.N.-T.L. Supervision: M.K.-M., M.S., S.K., H.O., T.A. and H.K. Validation: K.O., Yu.S. and H.K. Visualization: K.O. and Yu.S. Writing-original draft: K.O., Yu.S. and H.K. Writing-review and editing: All authors.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Ohdan, K., Suzuki, Y., Kawada-Matsuo, M. et al. Staphylococcus capitis strain producing dual bacteriocins, capidermicin and micrococcin P1, shows broad-spectrum antimicrobial activity. Sci Rep (2026). https://doi.org/10.1038/s41598-026-36393-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-36393-6