Staphylococcus (S.) aureus is an important causative agent of wound infections with increasing incidence in the past decades. Specifically, the emergence of methicillin-resistant S. aureus (MRSA) causes serious problems, especially in nosocomial infections. Therefore, there is an urgent need to develop of alternative or supportive antimicrobial therapeutic modalities to meet these challenges. Purified compounds from hops have previously shown promising antimicrobial effects against MRSA isolates in vitro. In this study, purified beta-acids from hops were tested for their potential antimicrobial and healing properties using a porcine model of wounds infected by MRSA. The results show highly significant antimicrobial effects of the active substance in both the powder and Ambiderman-based application forms compared to both no-treatment control and treatment with Framycoin. Moreover, the macroscopic evaluation of the wounds during the treatment using the standardized Wound Healing Continuum indicated positive effects of the beta-acids on the overall wound healing. This is further supported by the microscopic data, which showed a clear improvement of the inflammatory parameters in the wounds treated by beta-acids. Thus, using the porcine model, we demonstrate significant therapeutic effects of hops compounds in the management of wounds infected by MRSA. Beta-acids from hops, therefore, represent a suitable candidate for the treatment of non-responsive nosocomial tissue infections by MRSA.

Department of Epidemiology Faculty of Military Health Sciences University of Defence 500 01 Hradec Kralove Czech Republic

Department of Microbiology Faculty of Medicine and Dentistry University Hospital Palacky University 771 47 Olomouc Czech Republic

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence 500 01 Hradec Kralove Czech Republic

Food Research Institute 110 00 Prague Czech Republic

Hop Research Institute 438 01 Zatec Czech Republic

Institute of Clinical Microbiology Faculty of Medicine in Hradec Kralove Charles University and University Hospital 500 05 Hradec Kralove Czech Republic

Research Institute of Brewing and Malting 110 00 Prague Czech Republic

Thomayer Hospital 110 00 Prague Czech Republic

Zobrazit více v PubMed

Sakr A., Bregeon F., Mege J.L., Rolain J.M., Blin O. Staphylococcus aureus Nasal Colonization: An Update on Mechanisms, Epidemiology, Risk Factors, and Subsequent Infections. Front. Microbiol. 2018;9:2419. doi: 10.3389/fmicb.2018.02419. PubMed DOI PMC

Lone A.G., Atci E., Renslow R., Beyenal H., Noh S., Fransson B., Abu-Lail N., Park J.J., Gang D.R., Call D.R. Staphylococcus aureus induces hypoxia and cellular damage in porcine dermal explants. Infect. Immun. 2015;83:2531–2541. doi: 10.1128/IAI.03075-14. PubMed DOI PMC

McCaig L.F., McDonald L.C., Mandal S., Jernigan D.B. Staphylococcus aureus-associated skin and soft tissue infections in ambulatory care. Emerg. Infect. Dis. 2006;12:1715–1723. doi: 10.3201/eid1211.060190. PubMed DOI PMC

Turner N.A., Sharma-Kuinkel B.K., Maskarinec S.A., Eichenberger E.M., Shah P.P., Carugati M., Holland T.L., Fowler V.G., Jr. Methicillin-resistant Staphylococcus aureus: An overview of basic and clinical research. Nat. Rev. Microbiol. 2019;17:203–218. doi: 10.1038/s41579-018-0147-4. PubMed DOI PMC

Bogdanova K., Roderova M., Kolar M., Langova K., Dusek M., Jost P., Kubelkova K., Bostik P., Olsovska J. Antibiofilm activity of bioactive hop compounds humulone, lupulone and xanthohumol toward susceptible and resistant staphylococci. Res. Microbiol. 2018;169:127–134. doi: 10.1016/j.resmic.2017.12.005. PubMed DOI

Cermak P., Olsovska J., Mikyska A., Dusek M., Kadleckova Z., Vanicek J., Nyc O., Sigler K., Bostikova V., Bostik P. Strong antimicrobial activity of xanthohumol and other derivatives from hops (Humulus lupulus L.) on gut anaerobic bacteria. APMIS. 2017;125:1033–1038. doi: 10.1111/apm.12747. PubMed DOI

Roehrer S., Behr J., Stork V., Ramires M., Medard G., Frank O., Kleigrewe K., Hofmann T., Minceva M. Xanthohumol C. A minor bioactive hop compound: Production, purification strategies and antimicrobial test. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2018;1095:39–49. doi: 10.1016/j.jchromb.2018.07.018. PubMed DOI

Barington K., Dich-Jorgensen K., Jensen H.E. A porcine model for pathomorphological age assessment of surgically excised skin wounds. Acta Vet. Scand. 2018;60:33. doi: 10.1186/s13028-018-0387-3. PubMed DOI PMC

Dai T., Kharkwal G.B., Tanaka M., Huang Y.Y., Bil de Arce V.J., Hamblin M.R. Animal models of external traumatic wound infections. Virulence. 2011;2:296–315. doi: 10.4161/viru.2.4.16840. PubMed DOI PMC

Jensen L.K., Johansen A.S.B., Jensen H.E. Porcine Models of Biofilm Infections with Focus on Pathomorphology. Front. Microbiol. 2017;8:1961. doi: 10.3389/fmicb.2017.01961. PubMed DOI PMC

Meyer W., Schwarz R., Neurand K. The skin of domestic mammals as a model for the human skin, with special reference to the domestic pig. Curr. Probl. Dermatol. 1978;7:39–52. doi: 10.1159/000401274. PubMed DOI

Zurawski D.V., Black C.C., Alamneh Y.A., Biggemann L., Banerjee J., Thompson M.G., Wise M.C., Honnold C.L., Kim R.K., Paranavitana C., et al. A Porcine Wound Model of Acinetobacter baumannii Infection. Adv. Wound Care (New Rochelle) 2019;8:14–27. doi: 10.1089/wound.2018.0786. PubMed DOI PMC

Bogdanova K., Kolar M., Langova K., Dusek M., Mikyska A., Bostikova V., Bostik P., Olsovska J. Inhibitory effect of hop fractions against Gram-positive multi-resistant bacteria. A pilot study. Biomed. Pap. Med. Fac. Univ. Palacky. Olomouc Czech Repub. 2018 doi: 10.5507/bp.2018.026. PubMed DOI

Bacitracin—Natural Peptide with Minimal Resistance Issues. [(accessed on 15 May 2018)]; Available online: https://www.thepigsite.com/articles/bacitracin-natural-peptide-with-minimal-resistance-issues.

Gray D., White R., Cooper P., Kingsley A. Applied Wound Management and Using the Wound Healing Continuum in Practice. Wound Essent. 2010;5:131–139.

Kolar M., Cermak P., Hobzova L., Bogdanova K., Neradova K., Mlynarcik P., Bostik P. Antibiotic Resistance in Nosocomial Bacteria Isolated from Infected Wounds of Hospitalized Patients in Czech Republic. Antibiotics (Basel) 2020;9:342. doi: 10.3390/antibiotics9060342. PubMed DOI PMC

Dou J.L., Jiang Y.W., Xie J.Q., Zhang X.G. New is old, and old is new: Recent advances in antibiotic-based, antibiotic-free and ethnomedical treatments against methicillin-resistant Staphylococcus aureus wound infections. Int. J. Mol. Sci. 2016;17:617. doi: 10.3390/ijms17050617. PubMed DOI PMC

Nusbaum A.G., Gil J., Rippy M.K., Warne B., Valdes J., Claro A., Davis S.C. Effective method to remove wound bacteria: Comparison of various debridement modalities in an in vivo porcine model. J. Surg. Res. 2012;176:701–707. doi: 10.1016/j.jss.2011.11.1040. PubMed DOI

Lio P.A., Kaye E.T. Topical antibacterial agents. Infect. Dis. Clin. N. Am. 2009;23:945–963. doi: 10.1016/j.idc.2009.06.006. PubMed DOI

Arias C.A., Murray B.E. Antibiotic-resistant bugs in the 21st century—A clinical super-challenge. N. Engl. J. Med. 2009;360:439–443. doi: 10.1056/NEJMp0804651. PubMed DOI

Boucher H.W., Talbot G.H., Bradley J.S., Edwards J.E., Gilbert D., Rice L.B., Scheld M., Spellberg B., Bartlett J. Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America. Clin. Infect. Dis. 2009;48:1–12. doi: 10.1086/595011. PubMed DOI

Spellberg B., Powers J.H., Brass E.P., Miller L.G., Edwards J.E., Jr. Trends in antimicrobial drug development: Implications for the future. Clin. Infect. Dis. 2004;38:1279–1286. doi: 10.1086/420937. PubMed DOI

Edmondson M., Newall N., Carville K., Smith J., Riley T.V., Carson C.F. Uncontrolled, open-label, pilot study of tea tree (Melaleuca alternifolia) oil solution in the decolonisation of methicillin-resistant Staphylococcus aureus positive wounds and its influence on wound healing. Int. Wound J. 2011;8:375–384. doi: 10.1111/j.1742-481X.2011.00801.x. PubMed DOI PMC

Jenkins R., Cooper R. Improving antibiotic activity against wound pathogens with manuka honey in vitro. PLoS ONE. 2012;7:e45600. doi: 10.1371/journal.pone.0045600. PubMed DOI PMC

Davis S.C., Li J., Gil J., Head C., Valdes J., Glinos G.D., Solis M., Higa A., Pastar I. Preclinical evaluation of a novel silver gelling fiber dressing on Pseudomonas aeruginosa in a porcine wound infection model. Wound Repair Regen. 2019;27:360–365. doi: 10.1111/wrr.12718. PubMed DOI

Hadad I., Johnstone B.H., Brabham J.G., Blanton M.W., Rogers P.I., Fellers C., Solomon J.L., Merfeld-Clauss S., DesRosiers C.M., Dynlacht J.R., et al. Development of a porcine delayed wound-healing model and its use in testing a novel cell-based therapy. Int J. Radiat. Oncol. Biol. Phys. 2010;78:888–896. doi: 10.1016/j.ijrobp.2010.05.002. PubMed DOI

Malmsjo M., Ingemansson R., Martin R., Huddleston E. Negative-pressure wound therapy using gauze or open-cell polyurethane foam: Similar early effects on pressure transduction and tissue contraction in an experimental porcine wound model. Wound Repair Regen. 2009;17:200–205. doi: 10.1111/j.1524-475X.2009.00461.x. PubMed DOI

Mokhtari A., Gustafsson R., Sjogren J., Nilsson J., Lindstedt S., Malmsjo M., Ingemansson R. Haemodynamic effects of -75 mmHg negative pressure therapy in a porcine sternotomy wound model. Int. Wound J. 2009;6:48–54. doi: 10.1111/j.1742-481X.2008.00566.x. PubMed DOI PMC

Dos Santos M.R., Alcaraz-Espinoza J.J., da Costa M.M., de Oliveira H.P. Usnic acid-loaded polyaniline/polyurethane foam wound dressing: Preparation and bactericidal activity. Mater. Sci. Eng. C Mater. Biol. Appl. 2018;89:33–40. doi: 10.1016/j.msec.2018.03.019. PubMed DOI

Lee J.W., Song K.Y. Evaluation of a polyurethane foam dressing impregnated with 3% povidone-iodine (Betafoam) in a rat wound model. Ann. Surg. Treat. Res. 2018;94:1–7. doi: 10.4174/astr.2018.94.1.1. PubMed DOI PMC

Lipsky B.A., Hoey C. Topical antimicrobial therapy for treating chronic wounds. Clin. Infect. Dis. 2009;49:1541–1549. doi: 10.1086/644732. PubMed DOI

Krofta K., Liskova H., Vrabcova S. Process for Preparing Pure Beta Acids of Hop. CZ303017B6. 2012 Feb 29;

Elmarsafi T., Garwood C.S., Steinberg J.S., Evans K.K., Attinger C.E., Kim P.J. Effect of semiquantitative culture results from complex host surgical wounds on dehiscence rates. Wound Repair Regen. 2017;25:210–216. doi: 10.1111/wrr.12509. PubMed DOI

Hashimoto S., Shime N. Evaluation of semi-quantitative scoring of Gram staining or semi-quantitative culture for the diagnosis of ventilator-associated pneumonia: A retrospective comparison with quantitative culture. J. Intensive Care. 2013;1:2. doi: 10.1186/2052-0492-1-2. PubMed DOI PMC

Jault P., Leclerc T., Jennes S., Pirnay J.P., Que Y.A., Resch G., Rousseau A.F., Ravat F., Carsin H., Le Floch R., et al. Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): A randomised, controlled, double-blind phase 1/2 trial. Lancet Infect. Dis. 2019;19:35–45. doi: 10.1016/S1473-3099(18)30482-1. PubMed DOI

Kallstrom G. Are quantitative bacterial wound cultures useful? J. Clin. Microbiol. 2014;52:2753–2756. doi: 10.1128/JCM.00522-14. PubMed DOI PMC

Kilkenny C., Browne W.J., Cuthi I., Emerson M., Altman D.G. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. Vet. Clin. Pathol. 2012;41:27–31. doi: 10.1016/j.joca.2012.02.010. PubMed DOI

Pejchal J., Novotny J., Marak V., Osterreicher J., Tichy A., Vavrova J., Sinkorova Z., Zarybnicka L., Novotna E., Chladek J., et al. Activation of p38 MAPK and expression of TGF-beta1 in rat colon enterocytes after whole body gamma-irradiation. Int. J. Radiat. Biol. 2012;88:348–358. doi: 10.3109/09553002.2012.654044. PubMed DOI

Pavlik V., Sobotka L., Pejchal J., Cepa M., Nesporova K., Arenbergerova M., Mrozkova A., Velebny V. Silver distribution in chronic wounds and the healing dynamics of chronic wounds treated with dressings containing silver and octenidine. FASEB J. 2021;35:e21580. doi: 10.1096/fj.202100065R. PubMed DOI

Whole genome sequencing and characterization of Pantoea agglomerans DBM 3797, endophyte, isolated from fresh hop (Humulus lupulus L.)