New Perspectives on Old and New Therapies of Staphylococcal Skin Infections: The Role of Biofilm Targeting in Wound Healing
Abstract
1. Introduction
2. Results
2.1. Antibiotics
2.1.1. Beta-Lactams
2.1.2. Macrolides
2.1.3. Teicoplanin
2.1.4. Daptomycin
2.1.5. Tigecycline
2.1.6. Dalbavancin
2.2. Quorum Sensing Inhibitors
2.2.1. RIP
2.2.2. F19, F12 and F1
2.2.3. FS10
2.3. Antimicrobial Peptides
2.3.1. Innate Defence Regulator (IDR)-1018
2.3.2. LL-37
2.3.3. SHAP1
2.3.4. DRGN-1
2.3.5. Dermaseptin Peptide2 (DMS-PS2)
2.3.6. Cell-Free Supernatant (CFS) of Lactobacillus plantarum USM8613
2.3.7. Def-1
2.4. Other Topical Dressing
Octenidine Dihydrochloride (OCT)
2.5. Antimicrobial Photo Dynamic Therapy (APDT)
2.5.1. RLP068/Cl
2.5.2. Curcumin Encapsulated in Silica Nanoparticles
2.5.3. Aminolevulinic Acid (ALA)
2.5.4. Hypericin Nanoparticles
2.5.5. Methylene Blue aPDT (MB-aPDT)
3. Discussion
4. Materials and Methods
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Humphreys, H.; Becker, K.; Dohmen, P.; Petrosillo, N.; Spencer, M.; van Rijen, M.; Wechsler-Fördös, A.; Pujol, M.; Dubouix, A.; Garau, J. Staphylococcus aureus and surgical site infections: Benefits of screening and decolonization before surgery. J. Hosp. Infect. 2016, 94, 295–304. [Google Scholar] [CrossRef]
- James, G.A.; Swogger, E.; Wolcott, R.; Pulcini, E.D.; Secor, P.; Sestrich, J.; Costerton, J.W.; Stewart, P.S. Biofilms in chronic wounds. Wound Repair Regen. 2007, 16, 37–44. [Google Scholar] [CrossRef] [PubMed]
- E Dowd, S.; Sun, Y.; Secor, P.R.; Rhoads, D.D.; Wolcott, B.M.; A James, G.; Wolcott, R.D. Survey of bacterial diversity in chronic wounds using Pyrosequencing, DGGE, and full ribosome shotgun sequencing. BMC Microbiol. 2008, 8, 43. [Google Scholar] [CrossRef] [PubMed]
- Diekema, D.J.; Pfaller, M.A.; Schmitz, F.J.; Smayevsky, J.; Bell, J.; Jones, R.N.; Beach, M.; SENTRY Partcipants Group. Survey of infections due to Staphylococcus species: Frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin. Infect. Dis. 2001, 32 (Suppl. 2), S114–S132. [Google Scholar] [PubMed]
- Fridkin, S.K.; Hageman, J.C.; Morrison, M.; Sanza, L.T.; Como-Sabetti, K.; Jernigan, J.A.; Harriman, K.; Harrison, L.H.; Lynfield, R.; Farley, M.M. Methicillin-Resistant Staphylococcus aureus Disease in Three Communities. N. Engl. J. Med. 2005, 352, 1436–1444. [Google Scholar] [CrossRef] [PubMed]
- Malone, M.; Bjarnsholt, T.; McBain, A.J.; James, G.A.; Stoodley, P.; Leaper, D.; Tachi, M.; Schultz, G.; Swanson, T.; Wolcott, R.D. The prevalence of biofilms in chronic wounds: A systematic review and meta-analysis of published data. J. Wound Care 2017, 26, 20–25. [Google Scholar] [CrossRef] [PubMed]
- Norris, G.R.; Checketts, J.X.; Scott, J.T.; Vassar, M.; Norris, B.L.; Giannoudis, P.V. Prevalence of Deep Surgical Site Infection After Repair of Periarticular Knee Frac-tures: A Systematic Review and Meta-analysis. JAMA Netw. Open 2019, 2, e199951. [Google Scholar] [CrossRef]
- Wolcott, R. Disrupting the biofilm matrix improves wound healing outcomes. J. Wound Care 2015, 24, 366–371. [Google Scholar] [CrossRef] [PubMed]
- Percival, S.; Mccarty, S.M.; A Lipsky, B. Biofilms and Wounds: An Overview of the Evidence. Adv. Wound Care 2015, 4, 373–381. [Google Scholar] [CrossRef]
- Barki, K.G.; DAS, A.; Dixith, S.; Das Ghatak, P.; Mathew-Steiner, S.; Schwab, E.; Khanna, S.; Wozniak, D.J.; Roy, S.; Sen, C.K. Electric Field Based Dressing Disrupts Mixed-Species Bacterial Biofilm Infection and Restores Functional Wound Healing. Ann. Surg. 2019, 269, 756–766. [Google Scholar] [CrossRef] [PubMed]
- Roy, S.; Elgharably, H.; Sinha, M.; Ganesh, K.; Chaney, S.; Mann, E.; Miller, C.; Khanna, S.; Bergdall, V.K.; Powell, H.; et al. Mixed-species biofilm compromises wound healing by disrupting epidermal barrier function. J. Pathol. 2014, 233, 331–343. [Google Scholar] [CrossRef]
- Kowalewska-Grochowska, K.; Richards, R.; Moysa, G.; Lam, K.; Costerton, J.; King, E. Guidewire Catheter Change in Central Venous Catheter Biofilm Formation in a Burn Population. Chest 1991, 100, 1090–1095. [Google Scholar] [CrossRef] [PubMed]
- Wolcott, R.; Costerton, J.W.; Raoult, D.; Cutler, S.J. The polymicrobial nature of biofilm infection. Clin. Microbiol. Infect. 2013, 19, 107–112. [Google Scholar] [CrossRef] [PubMed]
- Kranjec, C.; Morales Angeles, D.; Torrissen Mårli, M.; Fernández, L.; García, P.; Kjos, M.; Diep, D.B. Staphylococcal Biofilms: Challenges and Novel Therapeutic Perspectives. Antibiotics 2021, 10, 131. [Google Scholar] [CrossRef]
- Coates, R.; Moran, J.; Horsburgh, M.J. Staphylococci: Colonizers and pathogens of ma skin. Future Microbiol. 2014, 9, 75–91. [Google Scholar] [CrossRef]
- Schultz, G.S.; Sibbald, R.G.; Falanga, V.; Ayello, E.A.; Dowsett, C.; Harding, K.; Romanelli, M.; Ds, M.C.S.; Teot, L.; Vanscheidt, W. Wound bed preparation: A systematic approach to wound management. Wound Repair Regen. 2003, 11, S1–S28. [Google Scholar] [CrossRef] [PubMed]
- Roy, S.; Santra, S.; Das, A.; Dixith, S.; Sinha, M.; Ghatak, S.; Ghosh, N.; Banerjee, P.; Khanna, S.; Mathew-Steiner, S.; et al. Staphylococcus aureus Biofilm Infection Compromises Wound Healing by Causing Deficiencies in Granulation Tissue Collagen. Ann. Surg. 2020, 271, 1174–1185. [Google Scholar] [CrossRef]
- Sen, C.K.; Gordillo, G.M.; Roy, S.; Kirsner, R.; Lambert, L.; Hunt, T.K.; Gottrup, F.; Gurtner, G.C.; Longaker, M.T. Human skin wounds: A major and snowballing threat to public health and the economy. Wound Repair Regen. 2009, 17, 763–771. [Google Scholar] [CrossRef]
- Trengove, N.J.; Stacey, M.C.; Macauley, S.; Bennett, N.; Gibson, J.; Burslem, F.; Murphy, G.; Schultz, G. Analysis of the acute and chronic wound environments: The role of proteases and their inhibitors. Wound Repair Regen. 1999, 7, 442–452. [Google Scholar] [CrossRef]
- Rogers, K.L.; Fey, P.D.; Rupp, M.E. Coagulase-Negative Staphylococcal Infections. Infect. Dis. Clin. N. Am. 2009, 23, 73–98. [Google Scholar] [CrossRef]
- Argemi, X.; Hansmann, Y.; Riegel, P.; Pre’vost, G. Is Staphylococcus lugdunensis significant in clinical samples? J. Clin. Microbiol. 2017, 55, 3167–3174. [Google Scholar] [CrossRef]
- Jenkins, T.C.; Knepper, B.C.; Jason Moore, S.; Saveli, C.C.; Pawlowski, S.W.; Perlman, D.M.; McCollister, B.D.; Burman, W.J. Comparison of the microbiology and anti-biotic treatment among diabetic and nondiabetic patients hospitalized for cellulitis or cutaneous abscess. J. Hosp. Med. 2014, 9, 788–794. [Google Scholar] [CrossRef]
- Nguyen, K.T.; Seth, A.K.; Hong, S.J.; Geringer, M.R.; Xie, P.; Leung, K.P.; Mustoe, T.A.; Galiano, R.D. Deficient cytokine expression and neutrophil oxidative burst con-tribute to impaired cutaneous wound healing in diabetic biofilm-containing chronic wounds. Wound Repair. Regen. 2013, 21, 833–841. [Google Scholar] [CrossRef]
- Ammons, M.C. Anti-Biofilm Strategies and the Need for Innovations in Wound Care. Recent Patents Anti-Infective Drug Discov. 2010, 5, 10–17. [Google Scholar] [CrossRef]
- Percival, S.L.; Hill, K.E.; Williams, D.; Hooper, S.J.; Thomas, D.; Costerton, J.W. A review of the scientific evidence for biofilms in wounds. Wound Repair Regen. 2012, 20, 647–657. [Google Scholar] [CrossRef] [PubMed]
- Malik, A.; Mohammad, Z.; Ahmad, J. The diabetic foot infections: Biofilms and antimicrobial resistance. Diabetes Metab. Syndr. Clin. Res. Rev. 2013, 7, 101–107. [Google Scholar] [CrossRef] [PubMed]
- Percival, S.L.; Hill, K.E.; Malic, S.; Thomas, D.; Williams, D. Antimicrobial tolerance and the significance of persister cells in recalcitrant chronic wound biofilms. Wound Repair Regen. 2011, 19, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Bjarnsholt, T.; Kirketerp-Møller, K.; Jensen, P.; Madsen, K.G.; Phipps, R.K.; Krogfelt, K.A.; Høiby, N.; Givskov, M. Why chronic wounds will not heal: A novel hypothesis. Wound Repair Regen. 2008, 16, 2–10. [Google Scholar] [CrossRef] [PubMed]
- Watters, C.; DeLeon, K.; Trivedi, U.; Griswold, J.A.; Lyte, M.; Hampel, K.J.; Wargo, M.; Rumbaugh, K.P. Pseudomonas aeruginosa biofilms perturb wound resolution and antibiotic tolerance in diabetic mice. Med. Microbiol. Immunol. 2012, 202, 131–141. [Google Scholar] [CrossRef] [PubMed]
- Ortiz Balbuena, J.; Garcıa Madero, R.; Segovia Gomez, T.; Cantero Caballero, M.; Sánchez Romero, I.; Ramos Martínez, A. Microbiology of pressure and vascular ulcer infections. Rev. Esp. Geriatr. Gerontol. 2015, 50, 5–8. [Google Scholar] [CrossRef] [PubMed]
- Church, D.; Elsayed, S.; Reid, O.; Winston, B.; Lindsay, R. Burn wound infections. Clin. Microbiol. Rev. 2006, 19, 403–434. [Google Scholar] [CrossRef] [PubMed]
- Davis, S.C.; Ricotti, C.; Cazzaniga, A.; Welsh, E.; Eaglstein, W.H.; Mertz, P.M. Microscopic and physiologic evidence for biofilm-associated wound colonization in vivo. Wound Repair Regen. 2008, 16, 23–29. [Google Scholar] [CrossRef] [PubMed]
- Natsis, N.E.; Cohen, P.R. Coagulase-Negative Staphylococcus Skin and Soft Tissue Infections. Am. J. Clin. Dermatol. 2018, 19, 671–677. [Google Scholar] [CrossRef] [PubMed]
- Huda, S.; Azmiza, S.J.; Tengku, J.; Rosni, I. A review of Staphylococcal cassette chromosome mec (SCCmec) types in coagulasenegative staphylococci (CoNS) species. Malays. J. Med. Sci. 2017, 24, 7–18. [Google Scholar]
- Mohammed, Y.H.E.; Manukumar, H.; Rakesh, K.; Karthik, C.; Mallu, P.; Qin, H.-L. Vision for medicine: Staphylococcus aureus biofilm war and unlocking key’s for anti-biofilm drug development. Microb. Pathog. 2018, 123, 339–347. [Google Scholar] [CrossRef] [PubMed]
- Subrt, N.; Mesak, L.R.; Davies, J. Modulation of virulence gene expression by cell wall active antibiotics in Staphylococcus aureus. J. Antimicrob. Chemother. 2011, 66, 979–984. [Google Scholar] [CrossRef] [PubMed]
- Mirani, Z.A.; Jamil, N. Effect of sub-lethal doses of vancomycin and oxacillin on biofilm formation by vancomycin intermediate resistant Staphylococcus aureus. J. Basic Microbiol. 2010, 51, 191–195. [Google Scholar] [CrossRef] [PubMed]
- Haddadin, R.N.; Saleh, S.; Al-Adham, I.S.; Buultjens, T.E.; Collier, P.J. The effect of subminimal inhibitory concentrations of antibiotics on virulence factors expressed by Staphylococcus aureus biofilms. J. Appl. Microbiol. 2010, 108, 1281–1291. [Google Scholar] [CrossRef]
- Frank, K.L.; Reichert, E.J.; Piper, K.E.; Patel, R. In Vitro Effects of Antimicrobial Agents on Planktonic and Biofilm Forms of Staphylococcus lugdunensis Clinical Isolates. Antimicrob. Agents Chemother. 2007, 51, 888–895. [Google Scholar] [CrossRef] [PubMed]
- Kaplan, J.B.; Izano, E.A.; Gopal, P.; Karwacki, M.T.; Kim, S.; Bose, J.L.; Bayles, K.W.; Horswill, A.R. Low Levels of β-Lactam Antibiotics Induce Extracellular DNA Release and Biofilm Formation in Staphylococcus aureus. mBio 2012, 3, e00198-12. [Google Scholar] [CrossRef]
- Kaplan, J.B.; Jabbouri, S.; Sadovskaya, I. Extracellular DNA-dependent biofilm formation by Staphylococcus epidermidis RP62A in response to subminimal inhibitory concentrations of antibiotics. Res. Microbiol. 2011, 162, 535–541. [Google Scholar] [CrossRef] [PubMed]
- Pérez-Giraldo, C.; Rodríguez-Benito, A.; Morán, F.J.; Hurtado, C.; Blanco, M.T.; Gómez-García, A.C. In-vitro slime production by Staphylococcus epidermidis in presence of subinhibitory concentrations of ciprofloxacin, ofloxacin and sparfloxacin. J. Antimicrob. Chemother. 1994, 33, 845–848. [Google Scholar] [CrossRef] [PubMed]
- Majidpour, A.; Fathizadeh, S.; Afshar, M.; Rahbar, M.; Boustanshenas, M.; Heidarzadeh, M.; Arbabi, L. Dose-Dependent Effects of Common Antibiotics Used to Treat Staphylococcus aureus on Biofilm Formation. Iran J. Pathol. 2017, 12, 362–370. [Google Scholar] [CrossRef] [PubMed]
- Kirmusaoglu, S. Improved β-Lactam Susceptibility Against ica-Dependent Biofilm-Embedded Staphylococcus aureus by 2-Aminothiazole. Clin. Lab. 2020, 66. [Google Scholar] [CrossRef]
- Izano, E.A.; Amarante, M.A.; Kher, W.B.; Kaplan, J.B. Differential roles of poly-N acetylglucosamine surface polysaccharide and extracellular DNA in Staphylococcus aureus and Staphylococcus epidermidis biofilms. Appl. Environ. Microbiol. 2008, 74, 470–476. [Google Scholar] [CrossRef] [PubMed]
- Rice, K.C.; Mann, E.E.; Endres, J.L.; Weiss, E.C.; Cassat, J.E.; Smeltzer, M.; Bayles, K.W. The cidA murein hydrolase regulator contributes to DNA release and biofilm development in Staphylococcus aureus. Proc. Natl. Acad. Sci. USA 2007, 104, 8113–8118. [Google Scholar] [CrossRef]
- Houston, P.; Rowe, S.E.; Pozzi, C.; Waters, E.M.; O’Gara, J.P. Essential Role for the Major Autolysin in the Fibronectin-Binding Protein-Mediated Staphylococcus aureus Biofilm Phenotype. Infect. Immun. 2011, 79, 1153–1165. [Google Scholar] [CrossRef]
- Boles, B.R.; Horswill, A.R. agr-Mediated Dispersal of Staphylococcus aureus Biofilms. PLOS Pathog. 2008, 4, e1000052. [Google Scholar] [CrossRef]
- Kiedrowski, M.; Kavanaugh, J.S.; Malone, C.L.; Mootz, J.M.; Voyich, J.M.; Smeltzer, M.; Bayles, K.W.; Horswill, A.R. Nuclease Modulates Biofilm Formation in Community-Associated Methicillin-Resistant Staphylococcus aureus. PLoS ONE 2011, 6, e26714. [Google Scholar] [CrossRef]
- Fujimura, S.; Sato, T.; Hayakawa, S.; Kawamura, M.; Furukawa, E.; Watanabe, A. Antimicrobial efficacy of combined clarithromycin plus daptomycin against biofilms-formed methicillin-resistant Staphylococcus aureus on titanium medical devices. J. Infect. Chemother. 2015, 21, 756–759. [Google Scholar] [CrossRef]
- Fujimura, S.; Sato, T.; Kikuchi, T.; Zaini, J.; Gomi, K.; Watanabe, A. Efficacy of clarithromycin plus vancomycin in mice with implant-related infection caused by bio-film-forming Staphylococcus aureus. J. Orthop. Sci. 2009, 14, 658–661. [Google Scholar] [CrossRef]
- Yamasaki, O.; Akiyama, H.; Toi, Y.; Arata, J. A combination of roxithromycin and imipenem as an antimicrobial strategy against biofilms formed by Staphylococcus aureus. J. Antimicrob. Chemother. 2001, 48, 573–577. [Google Scholar] [CrossRef][Green Version]
- Pace, J.L.; Yang, G. Glycopeptides: Update on an old successful antibiotic class. Biochem. Pharmacol. 2006, 71, 968–980. [Google Scholar] [CrossRef] [PubMed]
- Ghiselli, R.; Cirioni, O.; Giacometti, A.; Scalise, A.; Simonetti, O.; Mocchegiani, F.; Orlando, F.; Goteri, G.; Della Vittoria, A.; Filosa, A.; et al. Comparative Efficacy of Topical Versus Systemic Teicoplanin in Experimental Model of Wound Infections. J. Surg. Res. 2008, 144, 74–81. [Google Scholar] [CrossRef] [PubMed]
- Hamed, K.; Gonzalez-Ruiz, A.; Seaton, A. Daptomycin: An evidence-based review of its role in the treatment of Gram-positive infections. Infect. Drug Resist. 2016, 9, 47–58. [Google Scholar] [CrossRef]
- He, W.-Q.; Zhang, Y.; Chen, H.; Zhao, C.; Wang, H. Efficacy and safety of daptomycin for the treatment of infectious disease: A meta-analysis based on randomized controlled trials. J. Antimicrob. Chemother. 2014, 69, 3181–3189. [Google Scholar] [CrossRef] [PubMed]
- Pierpaoli, E.; Orlando, F.; Cirioni, O.; Simonetti, O.; Giacometti, A.; Provinciali, M. Supplementation with tocotrienols from Bixa orellana improves the in vivo efficacy of daptomycin against methicillin-resistant Staphylococcus aureus in a mouse model of infected wound. Phytomedicine 2017, 36, 50–53. [Google Scholar] [CrossRef] [PubMed]
- Robbel, L.; Marahiel, M.A. Daptomycin, a Bacterial Lipopeptide Synthesized by a Nonribosomal Machinery. J. Biol. Chem. 2010, 285, 27501–27508. [Google Scholar] [CrossRef] [PubMed]
- Boudjemaa, R.; Briandet, R.; Revest, M.; Jacqueline, C.; Caillon, J.; Fontaine-Aupart, M.-P.; Steenkeste, K. New Insight into Daptomycin Bioavailability and Localization in Staphylococcus aureus Biofilms by Dynamic Fluorescence Imaging. Antimicrob. Agents Chemother. 2016, 60, 4983–4990. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Simonetti, O.; Lucarini, G.; Orlando, F.; Pierpaoli, E.; Ghiselli, R.; Provinciali, M.; Castelli, P.; Guerrieri, M.; Di Primio, R.; Offidani, A.; et al. Role of Daptomycin on Burn Wound Healing in an Animal Methicillin-Resistant Staphylococcus aureus Infection Model. Antimicrob. Agents Chemother. 2017, 61, e00606-17. [Google Scholar] [CrossRef]
- Silvestri, C.; Cirioni, O.; Arzeni, D.; Ghiselli, R.; Simonetti, O.; Orlando, F.; Ganzetti, G.; Staffolani, S.; Brescini, L.; Provinciali, M.; et al. In vitro activity and in vivo efficacy of tigecycline alone and in combination with daptomycin and rifampin against Gram-positive cocci isolated from surgical wound infection. Eur. J. Clin. Microbiol. Infect. Dis. 2011, 31, 1759–1764. [Google Scholar] [CrossRef] [PubMed]
- Szczuka, E.; Kaznowski, A. Antimicrobial activity of tigecycline alone or in combination with rifampin against Staphylococcus epidermidis in biofilm. Folia Microbiol. 2014, 59, 283–288. [Google Scholar] [CrossRef] [PubMed]
- Rose, W.E.; Poppens, P.T. Impact of biofilm on the in vitro activity of vancomycin alone and in combination with tigecycline and rifampicin against Staphylococcus aureus. J. Antimicrob. Chemother. 2008, 63, 485–488. [Google Scholar] [CrossRef]
- Aybar, Y.; Ozaras, R.; Besirli, K.; Engin, E.; Karabulut, E.; Salihoglu, T.; Mete, B.; Tabak, F.; Mert, A.; Tahan, G.; et al. Efficacy of tigecycline and vancomycin in experi-mental catheter-related Staphylococcus epidermidis infection: Microbiological and electron microscopic analysis of biofilm. Int. J. Antimicrob. Agents 2012, 39, 338–342. [Google Scholar] [CrossRef] [PubMed]
- Simonetti, O.; Morroni, G.; Ghiselli, R.; Orlando, F.; Brenciani, A.; Xhuvelaj, L.; Provinciali, M.; Offidani, A.; Guerrieri, M.; Giacometti, A.; et al. In vitro and in vivo activity of fosfomycin alone and in combination with rifampin and tigecycline against Gram-positive cocci isolated from surgical wound infections. J. Med. Microbiol. 2018, 67, 139–143. [Google Scholar] [CrossRef] [PubMed]
- Simonetti, O.; Cirioni, O.; Lucarini, G.; Orlando, F.; Ghiselli, R.; Silvestri, C.; Brescini, L.; Rocchi, M.; Provinciali, M.; Guerrieri, M.; et al. Tigecycline accelerates staphylococcal-infected burn wound healing through matrix metalloproteinase-9 modulation. J. Antimicrob. Chemother. 2011, 67, 191–201. [Google Scholar] [CrossRef] [PubMed]
- Simonetti, O.; Rizzetto, G.; Molinelli, E.; Cirioni, O.; Offidani, A. Review: A Safety Profile of Dalbavancin for On- and Off-Label Utilization. Ther. Clin. Risk Manag. 2021, 17, 223–232. [Google Scholar] [CrossRef] [PubMed]
- Silva, V.; Antão, H.S.; Guimarães, J.; Prada, J.; Pires, I.; Martins, A.; Maltez, L.; E Pereira, J.; Capelo, J.L.; Igrejas, G.; et al. Efficacy of dalbavancin against MRSA biofilms in a rat model of orthopaedic implant-associated infection. J. Antimicrob. Chemother. 2020, 75, 2182–2187. [Google Scholar] [CrossRef] [PubMed]
- Knafl, D.; Tobudic, S.; Cheng, S.C.; Bellamy, D.R.; Thalhammer, F. Dalbavancin reduces biofilms of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). Eur. J. Clin. Microbiol. Infect. Dis. 2016, 36, 677–680. [Google Scholar] [CrossRef] [PubMed]
- Simonetti, O.; Lucarini, G.; Morroni, G.; Orlando, F.; Lazzarini, R.; Zizzi, A.; Brescini, L.; Provinciali, M.; Giacometti, A.; Offidani, A.; et al. New Evidence and Insights on Dalbavancin and Wound Healing in a Mouse Model of Skin Infection. Antimicrob. Agents Chemother. 2020, 64, e02062-19. [Google Scholar] [CrossRef] [PubMed]
- Warrier, A.; Satyamoorthy, K.; Murali, T.S. Quorum-sensing regulation of virulence factors in bacterial biofilm. Future Microbiol. 2021, 16, 1003–1021. [Google Scholar] [CrossRef] [PubMed]
- Recsei, P.; Kreiswirth, B.; O’Reilly, M.; Schlievert, P.; Gruss, A.; Novick, R.P. Regulation of exoprotein gene expression in Staphylococcus aureus by agr. Mol. Gen. Genet. 1986, 202, 58–61. [Google Scholar] [CrossRef] [PubMed]
- Rooijakkers, S.H.; van Kessel, K.P.; van Strijp, J.A. Staphylococcal innate immune evasion. Trends Microbiol. 2005, 13, 596–601. [Google Scholar] [CrossRef] [PubMed]
- Foster, T.J.; Hook, M. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 1996, 6, 484–488. [Google Scholar] [CrossRef]
- Otto, M. Staphylococcus aureus toxins. Curr. Opin. Microbiol. 2014, 17, 32–37. [Google Scholar] [CrossRef]
- Zhang, L.; Lin, J.; Ji, G. Membrane Anchoring of the AgrD N-terminal Amphipathic Region Is Required for Its Processing to Produce a Quorum-sensing Pheromone in Staphylococcus aureus. J. Biol. Chem. 2004, 279, 19448–19456. [Google Scholar] [CrossRef] [PubMed]
- Thoendel, M.; Kavanaugh, J.S.; Flack, C.E.; Horswill, A.R. Peptide Signaling in the Staphylococci. Chem. Rev. 2010, 111, 117–151. [Google Scholar] [CrossRef] [PubMed]
- Ji, G.; Beavis, R.C.; Novick, R. Cell density control of staphylococcal virulence mediated by an octapeptide pheromone. Proc. Natl. Acad. Sci. USA 1995, 92, 12055–12059. [Google Scholar] [CrossRef]
- Otto, M.; Sussmuth, R.; Jung, G.; Gotz, F. Structure of the pheromone peptide of the Staphylococcus epidermidis agr system. FEBS Lett. 1998, 424, 89–94. [Google Scholar] [CrossRef]
- Krucke, G.W.; Grimes, D.E.; Grimes, R.M.; Dang, T.D. Antibiotic resistance in Staphylococcus aureus–containing cutaneous abscesses of patients with HIV. Am. J. Emerg. Med. 2009, 27, 344–347. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Balaban, N.; Cirioni, O.; Giacometti, A.; Ghiselli, R.; Braunstein, J.B.; Silvestri, C.; Mocchegiani, F.; Saba, V.; Scalise, G. Treatment of Staphylococcus aureus biofilm in-fection by the quorum-sensing inhibitor RIP. Antimicrob. Agents Chemother. 2007, 51, 2226–2229. [Google Scholar] [CrossRef]
- Kiran, M.D.; Adikesavan, N.V.; Cirioni, O.; Giacometti, A.; Silvestri, C.; Scalise, G.; Ghiselli, R.; Saba, V.; Orlando, F.; Shoham, M.; et al. Discovery of a quorum-sensing inhibitor of drug-resistant Staphylococcal infections by structure-based virtual screening. Mol. Pharmacol. 2008, 73, 1578–1586. [Google Scholar] [CrossRef] [PubMed]
- Giacometti, A.; Cirioni, O.; Ghiselli, R.; Dell’Acqua, G.; Orlando, F.; D’Amato, G.; Mocchegiani, F.; Silvestri, C.; Del Prete, M.S.; Rocchi, M.; et al. RNAIII-inhibiting peptide improves efficacy of clinically used antibiotics in a murine model of Staphylococcal sepsis. Peptides. 2005, 26, 169–175. [Google Scholar] [CrossRef] [PubMed]
- Cirioni, O.; Ghiselli, R.; Minardi, D.; Orlando, F.; Mocchegiani, F.; Silvestri, C.; Muzzonigro, G.; Saba, V.; Scalise, G.; Balaban, N.; et al. RNAIII-Inhibiting Peptide Affects Biofilm Formation in a Rat Model of Staphylococcal Ureteral Stent Infection. Antimicrob. Agents Chemother. 2007, 51, 4518–4520. [Google Scholar] [CrossRef]
- Simonetti, O.; Cirioni, O.; Mocchegiani, F.; Cacciatore, I.; Silvestri, C.; Baldassarre, L.; Orlando, F.; Castelli, P.; Provinciali, M.; Vivarelli, M.; et al. The Efficacy of the Quorum Sensing Inhibitor FS8 and Tigecycline in Preventing Prosthesis Biofilm in an Animal Model of Staphylococcal Infection. Int. J. Mol. Sci. 2013, 14, 16321–16332. [Google Scholar] [CrossRef] [PubMed]
- Ciulla, M.; Di Stefano, A.; Marinelli, L.; Cacciatore, I.; Di Biase, G. RNAIII Inhibiting Peptide (RIP) and Derivatives as Potential Tools for the Treatment of S. aureus Biofilm Infections. Curr. Top. Med. Chem. 2019, 18, 2068–2079. [Google Scholar] [CrossRef] [PubMed]
- Yarwood, J.M.; Schlievert, P.M. Quorum Sensing in Staphylococcus Infections. J. Clin. Investig. 2003, 112, 1620–1625. [Google Scholar] [CrossRef] [PubMed]
- Anguita-Alonso, P.; Giacometti, A.; Cirioni, O.; Ghiselli, R.; Orlando, F.; Saba, V.; Scalise, G.; Sevo, M.; Tuzova, M.; Patel, R.; et al. RNAIII-inhibiting-peptide-loaded polymethylmethacrylate prevents in vivo Staphylococcus aureus biofilm formation. Antimicrob. Agents Chemother. 2007, 51, 2594–2596. [Google Scholar] [CrossRef] [PubMed]
- Balaban, N.; Giacometti, A.; Cirioni, O.; Gov, Y.; Ghiselli, R.; Mocchegiani, F.; Viticchi, C.; Del Prete, M.S.; Saba, V.; Scalise, G.; et al. Use of the Quorum-Sensing Inhibitor RNAIII-Inhibiting Peptide to Prevent Biofilm Formation In Vivo by Drug-Resistant Staphylococcus epidermidis. J. Infect. Dis. 2003, 187, 625–630. [Google Scholar] [CrossRef] [PubMed]
- Balaban, N.; Goldkorn, T.; Nhan, R.T.; Dang, L.B.; Scott, S.; Ridgley, R.M.; Rasooly, A.; Wright, S.C.; Larrick, J.W.; Rasooly, R.; et al. Autoinducer of Virulence As a Target for Vaccine and Therapy Against Staphylococcus aureus. Science 1998, 280, 438–440. [Google Scholar] [CrossRef] [PubMed]
- Cirioni, O.; Giacometti, A.; Ghiselli, R.; Dell’Acqua, G.; Orlando, F.; Mocchegiani, F.; Silvestri, C.; Licci, A.; Saba, V.; Scalise, G.; et al. RNAIII-inhibiting peptide signifi-cantly reduces bacterial load and enhances the effect of antibiotics in the treatment of central venous catheter-associated Staphylococcus aureus infections. J. Infect. Dis. 2006, 193, 180–186. [Google Scholar] [CrossRef]
- Schierle, C.F.; De La Garza, M.; Mustoe, T.A.; Galiano, R.D. Staphylococcal biofilms impair wound healing by delaying reepithelialization in a murine cutaneous wound model. Wound Repair Regen. 2009, 17, 354–359. [Google Scholar] [CrossRef] [PubMed]
- Simonetti, O.; Cirioni, O.; Ghiselli, R.; Goteri, G.; Scalise, A.; Orlando, F.; Silvestri, C.; Riva, A.; Saba, V.; Madanahally, K.D.; et al. RNAIII-Inhibiting Peptide Enhances Healing of Wounds Infected with Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2008, 52, 2205–2211. [Google Scholar] [CrossRef]
- Naldini, A.; Carraro, F. Role of inflammatory mediators in angiogenesis. Curr. DrugTargets Inflamm. Allergy 2005, 4, 3–8. [Google Scholar] [CrossRef] [PubMed]
- Wolcott, R.D. Clinical Wound Healing Using Signal Inhibitors. In Control of Biofilm Infections by Signal Manipulation; Naomi, B., Ed.; Springer: Berlin/Heidelberg, Germany, 2008; Volume 2, pp. 157–170. [Google Scholar]
- Khodaverdian, V.; Pesho, M.; Truitt, B.; Bollinger, L.; Patel, P.; Nithianantham, S.; Yu, G.; Delaney, E.; Jankowsky, E.; Shoham, M. Discovery of antivirulence agents against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2013, 57, 3645–3652. [Google Scholar] [CrossRef]
- Kuo, D.; Yu, G.; Hoch, W.; Gabay, D.; Long, L.; Ghannoum, M.; Nagy, N.; Harding, C.V.; Viswanathan, R.; Shoham, M. Novel Quorum-Quenching Agents Promote Methicillin-Resistant Staphylococcus aureus (MRSA) Wound Healing and Sensitize MRSA to β-Lactam Antibiotics. Antimicrob. Agents Chemother. 2014, 59, 1512–1518. [Google Scholar] [CrossRef] [PubMed]
- Baldassarre, L.; Fornasari, E.; Cornacchia, C.; Cirioni, O.; Silvestri, C.; Castelli, P.; Giocometti, A.; Cacciatore, I. Discovery of novel RIP derivatives by alanine scanning for the treatment of S. aureus infections. MedChemComm 2013, 4, 1114–1117. [Google Scholar] [CrossRef]
- González, J.E.; Keshavan, N.D. Messing with Bacterial Quorum Sensing. Microbiol. Mol. Biol. Rev. 2006, 70, 859–875. [Google Scholar] [CrossRef]
- Dell’Acqua, G.; Giacometti, A.; Cirioni, O.; Ghiselli, R.; Saba, V.; Scalise, G.; Gov, Y.; Balaban, N. Suppression of Drug-Resistant Staphylococcal Infections by the Quorum-Sensing Inhibitor RNAIII-Inhibiting Peptide. J. Infect. Dis. 2004, 190, 318–320. [Google Scholar] [CrossRef] [PubMed]
- Simonetti, O.; Cirioni, O.; Cacciatore, I.; Baldassarre, L.; Orlando, F.; Pierpaoli, E.; Lucarini, G.; Orsetti, E.; Provinciali, M.; Fornasari, E.; et al. Efficacy of the Quorum Sensing Inhibitor FS10 Alone and in Combination with Tigecycline in an Animal Model of Staphylococcal Infected Wound. PLoS ONE 2016, 11, e0151956. [Google Scholar] [CrossRef]
- Donlan, R.M.; Costerton, J.W. Biofilms: Survival Mechanisms of Clinically Relevant Microorganisms. Clin. Microbiol. Rev. 2002, 15, 167–193. [Google Scholar] [CrossRef]
- Kang, H.-K.; Kim, C.; Seo, C.H.; Park, Y. The therapeutic applications of antimicrobial peptides (AMPs): A patent review. J. Microbiol. 2016, 55, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Mookherjee, N.; Hancock, R.E.W. Cationic host defence peptides: Innate immune regulatory peptides as a novel approach for treating infections. Experientia 2007, 64, 922–933. [Google Scholar] [CrossRef] [PubMed]
- Koczulla, R.; von Degenfeld, G.; Kupatt, C.; Krotz, F.; Zahler, S.; Gloe, T.; Issbrücker, K.; Unterberger, P.; Zaiou, M.; Lebherz, C.; et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J. Clin. Investig. 2003, 111, 1665–1672. [Google Scholar] [CrossRef]
- Mookherjee, N.; Brown, K.L.; Bowdish, D.M.; Doria, S.; Falsafi, R.; Hokamp, K.; Roche, F.M.; Mu, R.; Doho, G.H.; Pistolic, J.; et al. Modulation of the TLRmediated in-flammatory response by the endogenous human host defense peptide LL-37. J. Immunol. 2006, 176, 2455–2464. [Google Scholar] [CrossRef] [PubMed]
- Shaykhiev, R.; Beisswenger, C.; Kändler, K.; Senske, J.; Püchner, A.; Damm, T.; Behr, J.; Bals, R. Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure. Am. J. Physiol. Cell. Mol. Physiol. 2005, 289, L842–L848. [Google Scholar] [CrossRef] [PubMed]
- Niyonsaba, F.; Ushio, H.; Nakano, N.; Ng, W.; Sayama, K.; Hashimoto, K.; Nagaoka, I.; Okumura, K.; Ogawa, H. Antimicrobial peptides human beta-1s stimulate epi-dermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. J. Investig. Dermatol. 2007, 127, 594–604. [Google Scholar] [CrossRef]
- Cirioni, O.; Wu, G.; Li, L.; Orlando, F.; Silvestri, C.; Ghiselli, R.; Shen, Z.; Scalise, A.; Gabrielli, E.; Scuppa, D.; et al. S-thanatin enhances the efficacy of tigecycline in an experimental rat model of polymicrobial peritonitis. Peptides 2010, 31, 1231–1236. [Google Scholar] [CrossRef]
- Simonetti, O.; Arzeni, D.; Ganzetti, G.; Silvestri, C.; Cirioni, O.; Gabrielli, E.; Castelletti, S.; Kamysz, W.; Kamysz, E.; Scalise, G.; et al. In vitro activity of the lipopeptide derivative (Pal-Lys-Lys-NH), alone and in combination with antifungal agents, against clinical isolates of dermatophytes. Br. J. Dermatol. 2009, 161, 249–252. [Google Scholar] [CrossRef] [PubMed]
- Simonetti, O.; Cirioni, O.; Ghiselli, R.; Goteri, G.; Orlando, F.; Monfregola, L.; Luca, S.; Zizzi, A.; Silvestri, C.; Veglia, G.; et al. Antimicrobial properties of distinctin in an experimental model of MRSA-infected wounds. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31, 3047–3055. [Google Scholar] [CrossRef]
- Park, S.-C.; Park, Y.; Hahm, K.-S. The Role of Antimicrobial Peptides in Preventing Multidrug-Resistant Bacterial Infections and Biofilm Formation. Int. J. Mol. Sci. 2011, 12, 5971–5992. [Google Scholar] [CrossRef]
- De La Fuente-Núñez, C.; Reffuveille, F.; Haney, E.F.; Straus, S.; Hancock, R. Broad-Spectrum Anti-biofilm Peptide That Targets a Cellular Stress Response. PLoS Pathog. 2014, 10, e1004152. [Google Scholar] [CrossRef] [PubMed]
- Reffuveille, F.; De La Fuente-Núñez, C.; Mansour, S.; Hancock, R.E.W. A Broad-Spectrum Antibiofilm Peptide Enhances Antibiotic Action against Bacterial Biofilms. Antimicrob. Agents Chemother. 2014, 58, 5363–5371. [Google Scholar] [CrossRef] [PubMed]
- Etayash, H.; Pletzer, D.; Kumar, P.; Straus, S.K.; Hancock, R. Cyclic Derivative of Host-Defense Peptide IDR-1018 Improves Proteolytic Stability, Suppresses Inflammation, and Enhances In Vivo Activity. J. Med. Chem. 2020, 63. [Google Scholar] [CrossRef] [PubMed]
- Niyonsaba, F.; Kiatsurayanon, C.; Chieosilapatham, P.; Ogawa, H. Friends or Foes? Host defense (antimicrobial) peptides and proteins in human skin diseases. Exp. Dermatol. 2017, 26, 989–998. [Google Scholar] [CrossRef] [PubMed]
- Heilborn, J.D.; Nilsson, M.F.; Sorensen, O.E.; Ståhle-Bäckdahl, M.; Kratz, G.; Borregaard, N. The Cathelicidin Anti-Microbial Peptide LL-37 is Involved in Re-Epithelialization of Human Skin Wounds and is Lacking in Chronic Ulcer Epithelium. J. Investig. Dermatol. 2003, 120, 379–389. [Google Scholar] [CrossRef]
- Carretero, M.; Escámez, M.J.; García, M.; Duarte, B.; Holguín, A.; Retamosa, L.; Jorcano, J.L.; del Río, M.; Larcher, F. In vitro and In vivo Wound Healing-Promoting Activities of Human Cathelicidin LL-37. J. Investig. Dermatol. 2008, 128, 223–236. [Google Scholar] [CrossRef]
- Ramos, R.; Silva, J.P.; Rodrigues, A.C.; Costa, R.; Guardão, L.; Schmitt, F.; Soares, R.; Vilanova, M.; Domingues, L.; Gama, M. Wound healing activity of the human an-timicrobial peptide LL37. Peptides 2011, 32, 1469–1476. [Google Scholar] [CrossRef]
- Overhage, J.; Campisano, A.; Bains, M.; Torfs, E.C.W.; Rehm, B.; Hancock, R.E.W. Human Host Defense Peptide LL-37 Prevents Bacterial Biofilm Formation. Infect. Immun. 2008, 76, 4176–4182. [Google Scholar] [CrossRef] [PubMed]
- Simonetti, O.; Cirioni, O.; Goteri, G.; Lucarini, G.; Kamysz, E.; Kamysz, W.; Orlando, F.; Rizzetto, G.; Molinelli, E.; Morroni, G.; et al. Efficacy of the cathelicidin LL-37 in a MRSA wound infection mice model. Antibiotics 2021, in press. [Google Scholar] [CrossRef] [PubMed]
- Park, I.Y.; Cho, J.H.; Kim, K.S.; Kim, Y.-B.; Kim, M.S.; Kim, S.C. Helix Stability Confers Salt Resistance upon Helical Antimicrobial Peptides. J. Biol. Chem. 2004, 279, 13896–13901. [Google Scholar] [CrossRef]
- Pasupuleti, M.; Schmidtchen, A.; Chalupka, A.; Ringstad, L.; Malmsten, M. End-Tagging of Ultra-Short Antimicrobial Peptides by W/F Stretches to Facilitate Bacterial Killing. PLoS ONE 2009, 4, e5285. [Google Scholar] [CrossRef] [PubMed]
- Sieprawska-Lupa, M.; Mydel, P.; Krawczyk, K.; Wojcik, K.; Puklo, M.; Lupa, B.; Suder, P.; Silberring, J.; Reed, M.; Pohl, J.; et al. Degradation of human antimicrobial pep-tide LL-37 by Staphylococcus aureus-derived proteinases. Antimicrob. Agents Chemother. 2004, 48, 4673–4679. [Google Scholar] [CrossRef] [PubMed]
- Kim, D.J.; Lee, Y.W.; Park, M.K.; Shin, J.R.; Lim, K.J.; Cho, J.H.; Kim, S.C. Efficacy of the designer antimicrobial peptide SHAP1 in wound healing and wound infection. Amino Acids 2014, 46, 2333–2343. [Google Scholar] [CrossRef]
- Tokumaru, S.; Sayama, K.; Shirakata, Y.; Komatsuzawa, H.; Ouhara, K.; Hanakawa, Y.; Yahata, Y.; Dai, X.; Tohyama, M.; Nagai, H.; et al. Induction of keratinocyte mi-gration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J. Immunol. 2005, 175, 4662–4668. [Google Scholar] [CrossRef] [PubMed]
- Rawlings, N.D.; Barrett, A.J.; Bateman, A. MEROPS: The peptidase database. Nucleic Acids Res. 2010, 38, D227–D233. [Google Scholar] [CrossRef]
- Chung, E.M.C.; Dean, S.N.; Propst, C.N.; Bishop, B.M.; Van Hoek, M.L. Komodo dragon-inspired synthetic peptide DRGN-1 promotes wound-healing of a mixed-biofilm infected wound. NPJ Biofilms Microbiomes 2017, 3, 1–13. [Google Scholar] [CrossRef]
- Song, X.; Pan, H.; Wang, H.; Liao, X.; Sun, D.; Xu, K.; Chen, T.; Zhang, X.; Wu, M.; Wu, D.; et al. Identification of new dermaseptins with self-assembly tendency: Membrane disruption, biofilm eradication, and infected wound healing efficacy. Acta Biomater. 2020, 109, 208–219. [Google Scholar] [CrossRef]
- Ong, J.S.; Taylor, T.D.; Yong, C.C.; Khoo, B.Y.; Sasidharan, S.; Choi, S.B.; Ohno, H.; Liong, M.T. Lactobacillus plantarum USM8613 Aids in Wound Healing and Suppresses Staphylococcus aureus Infection at Wound Sites. Probiotics Antimicrob. Proteins 2020, 12, 125–137. [Google Scholar] [CrossRef]
- Sojka, M.; Valachova, I.; Bucekova, M.; Majtan, J. Antibiofilm efficacy of honey and bee-derived defensin-1 on multispecies wound biofilm. J. Med. Microbiol. 2016, 65, 337–344. [Google Scholar] [CrossRef]
- Huang, J.; Fan, Q.; Guo, M.; Wu, M.; Wu, S.; Shen, S.; Wang, X.; Wang, H. Octenidine dihydrochloride treatment of a meticillin-resistant Staphylococcus aureus biofilm-infected mouse wound. J. Wound Care 2021, 30, 106–114. [Google Scholar] [CrossRef]
- Tavares, A.; Carvalho, C.M.B.; Faustino, M.A.; Neves, M.G.P.M.S.; Tomé, J.P.C.; Tomé, A.C.; Cavaleiro, J.A.S.; Cunha, A.; Gomes, N.C.M.; Alves, E.; et al. Antimicrobial Photodynamic Therapy: Study of Bacterial Recovery Viability and Potential Development of Resistance after Treatment. Mar. Drugs 2010, 8, 91–105. [Google Scholar] [CrossRef] [PubMed]
- Hamblin, M.R.; Hasan, T. Photodynamic therapy: A new antimicrobial approach to infectious disease? Photochem. Photobiol. Sci. 2004, 3, 436–450. [Google Scholar] [CrossRef]
- Silva, E.F.F.; Serpa, C.; Dąbrowski, J.M.; Monteiro, C.J.P.; Formosinho, S.J.; Stochel, G.; Urbanska, K.; Simões, S.; Pereira, M.M.; Arnaut, L.G. Mechanisms of Singlet-Oxygen and Superoxide-Ion Generation by Porphyrins and Bacteriochlorins and their Implications in Photodynamic Therapy. Chem.-Eur. J. 2010, 16, 9273–9286. [Google Scholar] [CrossRef]
- Sharman, W.M.; Allen, C.M.; van Lier, J.E. Photodynamic therapeutics: Basic principles and clinical applications. Drug Discov. Today 1999, 4, 507–517. [Google Scholar] [CrossRef]
- Wainwright, M. Photodynamic antimicrobial chemotherapy (PACT). J. Antimicrob. Chemother. 1998, 42, 13–28. [Google Scholar] [CrossRef]
- Zeina, B.; Greenman, J.; Purcell, W.; Das, B. Killing of cutaneous microbial species by photodynamic therapy. Br. J. Dermatol. 2001, 144, 274–278. [Google Scholar] [CrossRef] [PubMed]
- Pérez, C.; Zúñiga, T.; Palavecino, C.E. Photodynamic therapy for treatment of Staphylococcus aureus infections. Photodiagnosis Photodyn. Ther. 2021, 34, 102285. [Google Scholar] [CrossRef]
- Cieplik, F.; Deng, D.; Crielaard, W.; Buchalla, W.; Hellwig, E.; Al-Ahmad, A.; Maisch, T. Antimicrobial Photodynamic Therapy—What We Know and What We Don’t. Crit. Rev. Microbiol. 2018, 44, 571–589. [Google Scholar] [CrossRef]
- Hu, X.; Huang, Y.; Wang, Y.; Wang, X.; Hamblin, M.R. Antimicrobial Photodynamic Therapy to Control Clinically Relevant Biofilm Infections. Front. Microbiol. 2018, 9, 1299. [Google Scholar] [CrossRef]
- Kwiatkowski, S.; Knap, B.; Przystupski, D.; Saczko, J.; Kędzierska, E.; Knap-Czop, K.; Kotlińska, J.; Michel, O.; Kotowski, K.; Kulbacka, J. Photodynamic Therapy—Mechanisms, Photosensitizers and Combinations. Biomed. Pharmacother. 2018, 106, 1098–1107. [Google Scholar] [CrossRef]
- Woźniak, A.; Grinholc, M. Combined Antimicrobial Activity of Photodynamic Inactivation and Antimicrobials–State of the Art. Front. Microbiol. 2018, 9, 930. [Google Scholar] [CrossRef]
- Fabris, C.; Soncin, M.; Mazzon, E.; Calzavara-Pinton, P.; Lia, F.; Giacomo, C.; Dei, D.; Tampucci, S.; Roncucci, G.; Jori, G. A novel tetracationic phthalocyanine as a potential skin phototherapeutic agent. Exp. Dermatol. 2005, 14, 675–683. [Google Scholar] [CrossRef] [PubMed]
- Simonetti, O.; Cirioni, O.; Orlando, F.; Alongi, C.; Lucarini, G.; Silvestri, C.; Zizzi, A.; Fantetti, L.; Roncucci, G.; Giacometti, A.; et al. Effectiveness of antimicrobial photodynamic therapy with a single treatment of RLP068/Cl in an experimental model of Staphylococcus aureus wound infection. Br. J. Dermatol. 2011, 164, 987–995. [Google Scholar] [CrossRef]
- Araújo, N.C.; Fontana, C.R.; Bagnato, V.S.; Gerbi, M.E.M. Photodynamic antimicrobial therapy of curcumin in biofilms and carious dentine. Lasers Med. Sci. 2013, 29, 629–635. [Google Scholar] [CrossRef]
- Lee, H.-J.; Kang, S.-M.; Jeong, S.-H.; Chung, K.-H.; Kim, B.-I. Antibacterial photodynamic therapy with curcumin and Curcuma xanthorrhiza extract against Streptococcus mutans. Photodiagnosis Photodyn. Ther. 2017, 20, 116–119. [Google Scholar] [CrossRef]
- Spaeth, A.; Graeler, A.; Maisch, T.; Plaetzer, K. CureCuma–cationic curcuminoids with improved properties and enhanced antimicrobial photodynamic activity. Eur. J. Med. Chem. 2018, 159, 423–440. [Google Scholar] [CrossRef]
- Araújo, T.S.D.; Rodrigues, P.L.F.; Santos, M.S.; de Oliveira, J.M.; Rosa, L.P.; Bagnato, V.S.; Blanco, K.C.; da Silva, F.C. Reduced methicillin-resistant Staphylococcus aureus biofilm formation in bone cavities by photodynamic therapy. Photodiagnosis Photodyn. Ther. 2018, 21, 219–223. [Google Scholar] [CrossRef] [PubMed]
- Méndez, D.A.C.; Gutierrez, E.; Lamarque, G.C.C.; Rizzato, V.L.; Buzalaf, M.A.R.; Machado, M.A.A.M.; Cruvinel, T. The effectiveness of curcumin-mediated antimicrobial photodynamic therapy depends on pre-irradiation and biofilm growth times. Photodiagn. Photodyn. Ther. 2019, 27, 474–480. [Google Scholar] [CrossRef]
- Mirzahosseinipour, M.; Khorsandi, K.; Hosseinzadeh, R.; Ghazaeian, M.; Shahidi, F.K. Antimicrobial photodynamic and wound healing activity of curcumin encapsu-lated in silica nanoparticles. Photodiagn. Photodyn. Ther. 2020, 29, 101639. [Google Scholar] [CrossRef] [PubMed]
- Lin, M.-H.; Lee, J.Y.-Y.; Pan, S.-C.; Wong, T.-W. Enhancing wound healing in recalcitrant leg ulcers with aminolevulinic acid-mediated antimicrobial photodynamic therapy. Photodiagn. Photodyn. Ther. 2020, 33, 102149. [Google Scholar] [CrossRef]
- Saddiqe, Z.; Naeem, I.; Maimoona, A. A review of the antibacterial activity of Hypericum perforatum L. J. Ethnopharmacol. 2010, 131, 511–521. [Google Scholar] [CrossRef]
- Jacobson, J.M.; Feinman, L.; Liebes, L.; Ostrow, N.; Koslowski, V.; Tobia, A.; Cabana, B.E.; Lee, D.; Spritzler, J.; Prince, A.M. Pharmacokinetics, safety, and antiviral ef-fects of hypericin, a derivative of St. John’s Wort Plant, in patients with chronic hepatitis C virus infection. Antimicrob. Agents Chemother. 2001, 45, 517–524. [Google Scholar] [CrossRef] [PubMed]
- Kadam, N.; Chaudhari, H.; Parikh, J.; Modi, V.; Kokil, S.; Balaramnav, V. De novo Combination Therapy in Retroviral Infection. Int. J. Virol. 2010, 6, 219–223. [Google Scholar] [CrossRef]
- García, I.; Ballesta, S.; Gilaberte, Y.; Rezusta, A.; Pascual, A. Antimicrobial photodynamic activity of hypericin against methicillin-susceptible and resistant Staphylococcus aureus biofilms. Futur. Microbiol. 2015, 10, 347–356. [Google Scholar] [CrossRef]
- Cheng, Y.; Burda, C. 2.01—Nanoparticles for photodynamic therapy. In Comprehensive Nanoscience and Technology; Andrews, D.L., Scholes, G.D., Wiederrecht, G.P., Eds.; Academic Press: Amsterdam, The Netherlands, 2011; pp. 1–28. [Google Scholar]
- Paszko, E.; Ehrhardt, C.; Senge, M.O.; Kelleher, D.P.; Reynolds, J.V. Nanodrug applications in photodynamic therapy. Photodiagn. Photodyn. Ther. 2011, 8, 14–29. [Google Scholar] [CrossRef] [PubMed]
- Nafee, N.; Youssef, A.; El-Gowelli, H.; Asem, H.; Kandil, S. Antibiotic-free nanotherapeutics: Hypericin nanoparticles thereof for improved in vitro and in vivo antimicrobial photodynamic therapy and wound healing. Int. J. Pharm. 2013, 454, 249–258. [Google Scholar] [CrossRef] [PubMed]
- Pérez, M.; Robres, P.; Moreno, B.; Bolea, R.; Verde, M.T.; Pérez-Laguna, V.; Aspiroz, C.; Gilaberte, Y.; Rezusta, A. Comparison of Antibacterial Activity and Wound Healing in a Superficial Abrasion Mouse Model of Staphylococcus aureus Skin Infection Using Photodynamic Therapy Based on Methylene Blue or Mupirocin or Both. Front. Med. 2021, 8. [Google Scholar] [CrossRef]
- De La Fuente-Núñez, C.; Korolik, V.; Bains, M.; Nguyen, U.; Breidenstein, E.B.M.; Horsman, S.; Lewenza, S.; Burrows, L.; Hancock, R. Inhibition of Bacterial Biofilm Formation and Swarming Motility by a Small Synthetic Cationic Peptide. Antimicrob. Agents Chemother. 2012, 56, 2696–2704. [Google Scholar] [CrossRef] [PubMed]
- Dean, S.N.; Bishop, B.M.; van Hoek, M.L. Natural and synthetic cathelicidin peptides with anti-microbial and anti-biofilm activity against Staphylococcus aureus. BMC Microbiol. 2011, 11, 114. [Google Scholar] [CrossRef] [PubMed]
- Ovchinnikov, K.V.; Kranjec, C.; Thorstensen, T.; Carlsen, H.; Diep, D.B. Successful Development of Bacteriocins into Therapeutic Formulation for Treatment of MRSA Skin Infection in a Murine Model. Antimicrob. Agents Chemother. 2020, 64. [Google Scholar] [CrossRef]
- Fernandez, J.; Martin-Serrano, A.; Gómez-Casanova, N.; Falanga, A.; Galdiero, S.; de la Mata, F.J.; Heredero-Bermejo, I.; Ortega, P. Effect of the Combination of Levofloxacin with Cationic Carbosilane Dendron and Peptide in the Prevention and Treatment of Staphylococcus aureus Biofilms. Polymers 2021, 13, 2127. [Google Scholar] [CrossRef] [PubMed]
- Cirioni, O.; Giacometti, A.; Ghiselli, R.; Dell’Acqua, G.; Gov, Y.; Kamysz, W.; Lukasiak, J.; Mocchegiani, F.; Orlando, F.; D’Amato, G.; et al. Prophylactic efficacy of topical temporin A and RNAIII-inhibiting peptide in a subcutaneous rat Pouch model of graft infection attributable to staphylococci with intermediate resistance to glycopeptides. Circulation 2003, 108, 767–771. [Google Scholar] [CrossRef] [PubMed]
- Golda, A.; Kosikowska-Adamus, P.; Kret, A.; Babyak, O.; Wójcik, K.; Dobosz, E.; Potempa, J.; Lesner, A.; Koziel, J. The Bactericidal Activity of Temporin Analogues Against Methicillin Resistant Staphylococcus aureus. Int. J. Mol. Sci. 2019, 20, 4761. [Google Scholar] [CrossRef] [PubMed]
- Kranjec, C.; Ovchinnikov, K.V.; Grønseth, T.; Ebineshan, K.; Srikantam, A.; Diep, D.B. A bacteriocin-based antimicrobial formulation to effectively disrupt the cell via-bility of methicillin-resistant Staphylococcus aureus (MRSA) biofilms. NPJ Biofilms Microbiomes 2020, 6, 58. [Google Scholar] [CrossRef] [PubMed]
- Twomey, E.; Hill, C.; Field, D.; Begley, M. Bioengineered Nisin Derivative M17Q Has Enhanced Activity against Staphylococcus epidermidis. Antibiotics 2020, 9, 305. [Google Scholar] [CrossRef]
- Yang, N.; Teng, D.; Mao, R.; Hao, Y.; Wang, X.; Wang, Z.; Wang, X.; Wang, J. A recombinant fungal defensin-like peptide-P2 combats multidrug-resistant Staphylococcus aureus and biofilms. Appl. Microbiol. Biotechnol. 2019, 103, 5193–5213. [Google Scholar] [CrossRef]
- Brackman, G.; De Meyer, L.; Nelis, H.; Coenye, T. Biofilm inhibitory and eradicating activity of wound care products against Staphylococcus aureus and Staphylococcus epidermidis biofilms in an in vitro chronic wound model. J. Appl. Microbiol. 2013, 114, 1833–1842. [Google Scholar] [CrossRef]
- Reynoso, E.; Ferreyra, D.D.; Durantini, E.N.; Spesia, M.B. Photodynamic inactivation to prevent and disrupt Staphylococcus aureus biofilm under different media conditions. Photodermatol. Photoimmunol. Photomed. 2019, 35, 322–331. [Google Scholar] [CrossRef]
- Halstead, F.D.; Thwaite, J.E.; Burt, R.; Laws, T.R.; Raguse, M.; Moeller, R.; Webber, M.A.; Oppenheim, B.A. Antibacterial Activity of Blue Light against Nosocomial Wound Pathogens Growing Planktonically and as Mature Biofilms. Appl. Environ. Microbiol. 2016, 82, 4006–4016. [Google Scholar] [CrossRef]
- Dai, T.; Gupta, A.; Huang, Y.; Sherwood, M.E.; Murray, C.K.; Vrahas, M.S.; Kielian, T.; Hamblin, M.R. Blue Light Eliminates Community-Acquired Methicillin-Resistant Staphylococcus aureusin Infected Mouse Skin Abrasions. Photomed. Laser Surg. 2013, 31, 531–538. [Google Scholar] [CrossRef] [PubMed]
- Belyi, Y.; Rybolovlev, I.; Polyakov, N.; Chernikova, A.; Tabakova, I.; Gintsburg, A. Staphylococcus Aureus Surface Protein G is An Immunodominant Protein and a Possible Target in An Anti-Biofilm Drug Development. Open Microbiol. J. 2018, 12, 94–106. [Google Scholar] [CrossRef] [PubMed]
- Domanski, P.J.; Patel, P.R.; Bayer, A.S.; Zhang, L.; Hall, A.E.; Syribeys, P.J.; Gorovits, E.L.; Bryant, D.; Vernachio, J.H.; Hutchins, J.T.; et al. Characterization of a Humanized Monoclonal Antibody Recognizing Clumping Factor A Expressed by Staphylococcus aureus. Infect. Immun. 2005, 73, 5229–5232. [Google Scholar] [CrossRef][Green Version]
- Tkaczyk, C.; Kasturirangan, S.; Minola, A.; Jones-Nelson, O.; Gunter, V.; Shi, Y.Y.; Rosenthal, K.; Aleti, V.; Semenova, E.; Warrener, P.; et al. Multimechanistic Mono-clonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach. Antimicrob. Agents Chemother. 2017, 61, e00629-17. [Google Scholar] [CrossRef] [PubMed]
- Varshney, A.K.; Kuzmicheva, G.A.; Bowling, R.A.; Sunley, K.M.; Bowling, R.A.; Kwan, T.-Y.; Mays, H.R.; Rambhadran, A.; Zhang, Y.; Martin, R.L.; et al. A natural human monoclonal antibody targeting Staphylococcus Protein A protects against Staphylococcus aureus bacteremia. PLoS ONE 2018, 13, e0190537. [Google Scholar] [CrossRef] [PubMed]
- França, A.; Vilanova, M.; Cerca, N.; Pier, G.B. Monoclonal Antibody Raised against PNAG Has Variable Effects on Static S. epidermidis Biofilm Accumulation In Vitro. Int. J. Biol. Sci. 2013, 9, 518–520. [Google Scholar] [CrossRef] [PubMed]
- Natan, M.; Banin, E. From Nano to Micro: Using nanotechnology to combat microorganisms and their multidrug resistance. FEMS Microbiol. Rev. 2017, 41, 302–322. [Google Scholar] [CrossRef] [PubMed]
- Banerjee, S.; Ghosh, D.; Vishakha, K.; Das, S.; Mondal, S.; Ganguli, A. Photodynamic antimicrobial chemotherapy (PACT) using riboflavin inhibits the mono and dual species biofilm produced by antibiotic resistant Staphylococcus aureus and Escherichia coli. Photodiagn. Photodyn. Ther. 2020, 32, 102002. [Google Scholar] [CrossRef]
- Ramasamy, M.; Lee, J. Recent Nanotechnology Approaches for Prevention and Treatment of Biofilm-Associated Infections on Medical Devices. BioMed Res. Int. 2016, 2016, 1851242. [Google Scholar] [CrossRef]
- Malaekeh-Nikouei, B.; Bazzaz, B.S.F.; Mirhadi, E.; Tajani, A.S.; Khameneh, B. The role of nanotechnology in combating biofilm-based antibiotic resistance. J. Drug Deliv. Sci. Technol. 2020, 60, 101880. [Google Scholar] [CrossRef]
- Stamsås, G.A.; Myrbråten, I.S.; Straume, D.; Salehian, Z.; Veening, J.-W.; Håvarstein, L.S.; Kjos, M. CozEa and CozEb play overlapping and essential roles in controlling cell division in Staphylococcus aureus. Mol. Microbiol. 2018, 109, 615–632. [Google Scholar] [CrossRef]
- DeFrancesco, A.S.; Masloboeva, N.; Syed, A.K.; Deloughery, A.; Bradshaw, N.; Li, G.-W.; Gilmore, M.S.; Walker, S.; Losick, R.M. Genome-wide screen for genes involved in eDNA release during biofilm formation by Staphylococcus aureus. Proc. Natl. Acad. Sci. USA 2017, 114, E5969–E5978. [Google Scholar] [CrossRef] [PubMed]
- Duarte, A.C.; Fernández, L.; De Maesschalck, V.; Gutiérrez, D.; Campelo, A.B.; Briers, Y.; Lavigne, R.; Rodríguez, A.; García, P. Synergistic action of phage phiIPLA-RODI and lytic protein CHAPSH3b: A combination strategy to target Staphylococcus aureus biofilms. npj Biofilms Microbiomes 2021, 7, 39. [Google Scholar] [CrossRef] [PubMed]
- Dickey, J.; Perrot, V. Adjunct phage treatment enhances the effectiveness of low antibiotic concentration against Staphylococcus aureus biofilms in vitro. PLoS ONE 2019, 14, e0209390. [Google Scholar] [CrossRef] [PubMed]
- Akturk, E.; Oliveira, H.; Santos, S.B.; Costa, S.; Kuyumcu, S.; Melo, L.D.R.; Azeredo, J. Synergistic action of phage and antibiotics: Parameters to enhance the killing efficacy against mono and dual-species biofilms. Antibiotics 2019, 8, 103. [Google Scholar] [CrossRef]
- Rahman, M.; Kim, S.; Kim, S.M.; Seol, S.Y.; Kim, J. Characterization of induced Staphylococcus aureus bacteriophage SAP-26 and its anti-biofilm activity with rifampicin. Biofouling 2011, 27, 1087–1093. [Google Scholar] [CrossRef] [PubMed]
Therapy | Experimental Model | Wound Healing Assessment | Histological Findings | Advantages/Disadvantages | |
---|---|---|---|---|---|
ANTIBIOTICS | |||||
Kirmusaoglu S. et al., 2020 [33] | Beta-lactams | In vitro, MRSA ATCC43300, MRSA, MSSA, beta-lactams combined with 2-aminothiazole as adjuvant | Not available | Not available |
|
Simonetti et al., 2008 [34] | Teicoplanin | In vivo murine model with MRSA infected skin wound; placebo vs. aPDT vs. aPDT + RLP068 vs. teicoplanin intra peritoneal (i.p.) vs. non infected | Better wound-healing response compared to placebo |
|
|
Simonetti et al., 2017 [35] | Daptomycin | In vivo murine model with S. aureus ATCC43300 infected skin wound (burn); daptomycin i.p. vs. teicoplanin i.p. vs. placebo vs. non infected | Better overall healing of Daptomycin group |
|
|
Simonetti et al., 2011 [36] | Tigecycline | In vivo murine model with S. aureus ATCC43300 infected skin wound (burn); uninfected control group vs. infected no treatment vs. tigecycline i.p. vs. teicoplanin i.p. | Tigecycline showed better impact on wound healing |
|
|
Simonetti et al., 2020 [38] | Dalbavancin | In vivo murine model with MRSA infected skin wound; vancomycin i.p. vs. dalbavancin i.p. vs. uninfected vs. untreated | faster healing after dalbavancin treatment |
|
|
QUORUM SENSING INHIBITORS | |||||
Schierle et al., 2009 [39] | RIP | In vivo murine model with S. aureus and S. epidermidis biofilm producers; uninfected vs. RIP topically (100 mcg for 7 days) vs. untreated | Better wound healing vs. untreated |
|
|
Simonetti et al., 2008 [40] | In vivo murine model with MRSA infected skin wound; topical RIP (20 mcg), teicoplanin i.p., allevyn, allevyn + teicoplanin i.p., topical RIP + teicoplanin i.p. | Better wound healing with topical RIP + teicoplanin |
|
| |
Kuo et al., 2014 [41] | F19,F12, and F1 | In vivo (1) MRSA-infected insect larvae; F19, F12 and F1 injection (20 mg/kg) (2) in vivo murine model with MRSA-infected wounds; topical F12 and F1 vs. untreated | (1) F19,F12, and F1 improved survival of larvae (2) F12 and F1 improved the speed of wound healing |
|
|
Simonetti et al., 2016 [42] | FS10 | in vivo murine model with MRSA and MSSA-infected wounds; topical FS10 (20mcg) + tigecycline i.p. (7 mg/kg) vs. monotherapy vs. untreated vs. uninfected | FS10 + tigecycline showed better wound healing and infection control |
|
|
ANTIMICROBIAL PEPTIDES | |||||
Etayash H. et al., 2020 [43] | IDR-1018 | In vivo murine model with MRSA infection abscess; IDR-1018 injected subcutaneously | Not available | Not available |
|
Carretero M. et al., 2008 [44] | LL-37 | In vivo murine model non infected wound, adenoviral transfer of LL-37 | Improved wound healing compared to untreated |
|
|
Kim DJ et al., 2014 [50] | SHAP1 | In vivo murine model with S. aureus (ATCC 29213) infected wounds; topical shap1 vs. LL-37 vs. PBS | Promote and accelerate wound healing |
|
|
Chung EMC et al., 2017 [51] | DRGN-1 | (1) in vivo murine model with S. aureus infected wound; Topical DRGN-1 vs. VK25 vs. LL-37 vs. PBS (2) in vivo murine model non-infected, Topical DRGN-1 vs. VK25 vs. PBS | (1–2) Wound healing significantly faster with DRGN-1, wound size considered | (1) skin layers were completely rehabilitated |
|
Song X. et al., 2020 [52] | DMS-PS2 | In vivo murine model with MRSA infected wounds; Topical MDS-PS2 vs. untreated | DMS-PS2 improved wound healing | Not available, clinically increased rate of re-epithelialisation |
|
Cell-free supernatant (CFS) of Lactobacillus plantarum USM8613 | (1) porcine skin wound model infected with S. aureus; CFS vs. untreated (2) in vivo murine model infected with S. aureus; CFS vs. untreated control | (2) CFS enhanced wound contraction percentage (54%) | (2) accelerated keratinocyte migration over the wound edge towards the centre area over time (2) achieved better wound closure and complete re-epithelisation |
| |
Sojka M. et al., 2016 [53] | Def-1 | In vitro Lubbock chronic wound biofilm model, S. aureus among other bacteria | Not available | Not available |
|
TOPICAL | |||||
Huang J. et al., 2021 [54] | Octenidine dihydrochloride | In vivo murine model with MRSA infected skin wound | Accelerated healing and reduced bacterial counts versus control (PBS) |
|
|
APDT | |||||
Simonetti et al., 2011 [55] | RLP068/Cl | In vivo murine model with MRSA-infected wound; RLP068/Cl + aPDT (689 nm) vs. untreated vs. teicoplanin i.p. | Better results in wound healing with RLP068/CI |
|
|
Mirzahosseinipour M. et al., 2020 [56] | Curcumin encapsulated in silica nanoparticles (CEN) | In vitro human dermal fibroblast culture infected with S. aureus; CEN + APDT (465 nm) vs. curcumin vs. untreated | CEN Improved human fibroblast activity | the denuded region of wounds treated with curcumin and CEN was narrower than that of untreated wounds (in vitro scratch assay) |
|
Lin et al., 2020 [57] | ALA | 3 patients with chronic leg ulcers resistant to conventional therapy (S. aureus isolated 1 patient); ALA + APDT | Clinically evident improvement without recurrences for 29 months | Not available |
|
Nafee et al., 2013 [58] | Hypericin nanoparticles (HN) | In vivo murine model with MRSA infected wound; HN vs. Hypericin vs. untreated | HN showed faster wound healing | better epithelialization, keratinization, and development of collagen fibres |
|
Pérez et al., 2021 [59] | Methylene Blue (MB)-aPDT | In vivo murine model with S. aureus ATCC29213 infected wound; Topical MB-APDT vs. mupirocin (MU) vs. MB-APDT + MU vs. untreated | MB-aPDT improves quick mild wound contraction at 24 h, better wound healing (reduction of size, crust loss) and cosmetics results (no scar). | mild acanthosis and mild undulation of the epidermis, a thicker dermis with moderate dermal fibrosis and more dilated follicles with abundant keratin and granulomatous inflammation. |
|
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 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
Simonetti, O.; Rizzetto, G.; Radi, G.; Molinelli, E.; Cirioni, O.; Giacometti, A.; Offidani, A. New Perspectives on Old and New Therapies of Staphylococcal Skin Infections: The Role of Biofilm Targeting in Wound Healing. Antibiotics 2021, 10, 1377. https://doi.org/10.3390/antibiotics10111377
Simonetti O, Rizzetto G, Radi G, Molinelli E, Cirioni O, Giacometti A, Offidani A. New Perspectives on Old and New Therapies of Staphylococcal Skin Infections: The Role of Biofilm Targeting in Wound Healing. Antibiotics. 2021; 10(11):1377. https://doi.org/10.3390/antibiotics10111377
Chicago/Turabian StyleSimonetti, Oriana, Giulio Rizzetto, Giulia Radi, Elisa Molinelli, Oscar Cirioni, Andrea Giacometti, and Annamaria Offidani. 2021. "New Perspectives on Old and New Therapies of Staphylococcal Skin Infections: The Role of Biofilm Targeting in Wound Healing" Antibiotics 10, no. 11: 1377. https://doi.org/10.3390/antibiotics10111377
APA StyleSimonetti, O., Rizzetto, G., Radi, G., Molinelli, E., Cirioni, O., Giacometti, A., & Offidani, A. (2021). New Perspectives on Old and New Therapies of Staphylococcal Skin Infections: The Role of Biofilm Targeting in Wound Healing. Antibiotics, 10(11), 1377. https://doi.org/10.3390/antibiotics10111377