Staphylococcus aureus Toxins: An Update on Their Pathogenic Properties and Potential Treatments
Abstract
:1. Introduction
2. Toxins Involved in the Pathogenicity of S. aureus
2.1. Staphylococcal Pore-Forming Toxins (PFTs)
2.1.1. Hemolysins
2.1.2. Panton-Valentine Leukocidin (PVL)
2.1.3. Phenol-Soluble Modulins (PSMs)
2.1.4. Epidermal Cell Differentiation Inhibitor (EDIN) Exotoxins
2.2. Exfoliative Toxins (ETs)
2.3. Superantigens (SAgs)
2.3.1. Staphylococcal Enterotoxins (SEs)
2.3.2. Toxic Shock Syndrome Toxin 1 (TSST-1)
Toxin | Biological Properties and Function | Associated Disease | References |
---|---|---|---|
α-hemolysin |
|
| [23,24,92,93] |
Panton–Valentine Leukocidin (PVL) |
|
| [30,31,94] |
Phenol-Soluble Modulins (PSMs) |
|
| [40,82,95,96] |
Epidermal Cell Differentiation Inhibitor (EDIN) |
|
| [53,54,66] |
Exfoliative Toxins (ETs) |
|
| [68,97] |
Staphylococcal Enterotoxins (SEs) |
|
| [19,81,85] |
Toxic Shock Syndrome Toxin 1 (TSST-1) |
|
| [82,90,91] |
3. Anti-Toxin Treatments
3.1. Antibodies
3.2. Nanoparticles
3.3. RNAIII-Inhibiting Peptides
3.4. Antimicrobial Peptides (AMPs)
3.5. Natural Compounds
3.6. Vaccines
3.7. Others
Treatment | Name | Target | References |
---|---|---|---|
Antibodies | MEDI4893 (suvratoxumab) | α-hemolysin | [98,99,100] |
AR-301 | α-hemolysin | [106] | |
ASN100 | α-hemolysin, Panton–Valentine leukocidin (PVL), LukAB, Ɣ-hemolysin AB (HlgAB), Ɣ-hemolysin CB (HlgCB), leukocidin ED (LukED) | [107] | |
LTM14 | α-hemolysin | [99] | |
IVIg | α-hemolysin, PVL | [112,113,114] | |
HuMAb-154 | Staphylococcal enterotoxin B (SEB) | [117] | |
20B1 | Staphylococcal enterotoxin B (SEB) | [118] | |
Nanoparticles | Sphingomyelin liposomes | Phenol-soluble modulins (PSMs) | [121] |
Cholesterol-containing sphingomyelin liposomes | α-hemolysin | [121] | |
Poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles covered with natural human erythrocyte membranes | α-hemolysin | [123] | |
RNAIII-inhibiting peptides | RNAIII-inhibiting peptides (RIP) | agr RNA transcripts | [128,129,130] |
Antimicrobial peptides | HNP3 | PVL | [141] |
Natural compounds | Cyclodextrin IB201 | α-hemolysin | [142] |
Aloe-emodin | α-hemolysin | [144] | |
Apigenin | α-hemolysin | [143] | |
Morin hydrate (2′,3,4′,5,7-pentahydroxyflavone) | α-hemolysin | [145] | |
Oroxylin glycosides (oroxin A (ORA), oroxin B (ORB), and oroxylin A 7-O-glucuronide (OLG)) | α-hemolysin | [146,147] | |
4-hydroxytyrosol Hidrox-12 | Staphylococcal enterotoxin A (SEA) | [148] | |
Solonamide B | Quorum-sensing peptide (AIP) | [149,150,151,152] | |
Isorhamnetin (3′-methoxy-3,4′,5,7-tetrahydroxyflavone) | α-hemolysin | [155] | |
Chrysin (5, 7-dihydroxyflavone) | α-hemolysin | [156] | |
Puerarin | α-hemolysin | [157] | |
Naringenin | agrA and hla expression | [158,159] | |
224C-F2 (Castanea sativa leaf) 430D-F5 (Schinus terebinthifolia berry) | agr expression | [161] | |
Ambuic acid | AgrB activity, RNAIII expression | [162] | |
Omega-hydroxyemodin (OHM) | AgrA | [163,164] | |
Vaccines | H35L | α-hemolysin | [165,166] |
IBT-VO2 | α-hemolysin, PVL, enterotoxins A and B, toxic shock syndrome toxin 1 (TSST-1) | [167] | |
StaphVax | PVL | [170] | |
STEBVax | SEB | [174] | |
Attenuated TSST-1 vaccine | TSST-1 | [175,176,177] | |
Others | Extracellular vesicles (EVs) | α-hemolysin, LukE | [181] |
Yeast display technology to create a soluble T-cell receptor | SEC, SEB | [180] |
4. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
- Wertheim, H.F.; Melles, D.C.; Vos, M.C.; van Leeuwen, W.; van Belkum, A.; Verbrugh, H.A.; Nouwen, J.L. The Role of Nasal Carriage in Staphylococcus aureus. Lancet Infect. Dis. 2005, 5, 751–762. [Google Scholar] [CrossRef]
- Hanselman, B.A.; Kruth, S.A.; Rousseau, J.; Weese, J.S. Coagulase Positive Staphylococcal Colonization of Humans and Their Household Pets. Can. Vet. J. 2009, 50, 954–958. [Google Scholar] [PubMed]
- Tong, S.Y.C.; Davis, J.S.; Eichenberger, E.; Holland, T.L.; Fowler, V.G. Staphylococcus aureus Infections: Epidemiology, Pathophysiology, Clinical Manifestations, and Management. Clin. Microbiol. Rev. 2015, 28, 603–661. [Google Scholar] [CrossRef] [Green Version]
- Antimicrobial Resistance in the EU/EEA (EARS-Net)—Annual Epidemiological Report for 2019. Available online: https://www.ecdc.europa.eu/en/publications-data/surveillance-antimicrobial-resistance-europe-2019 (accessed on 23 August 2021).
- Borg, M.A.; Camilleri, L. What Is Driving the Epidemiology of Methicillin-Resistant Staphylococcus aureus Infections in Europe? Microb. Drug Resist. 2020, 27, 889–894. [Google Scholar] [CrossRef] [PubMed]
- Lowy, F.D. Staphylococcus aureus Infections. N. Engl. J. Med. 1998, 339, 520–532. [Google Scholar] [CrossRef] [PubMed]
- Tam, K.; Torres, V.J. Staphylococcus aureus Secreted Toxins and Extracellular Enzymes. Microbiol. Spectr. 2019, 7, 16. [Google Scholar] [CrossRef]
- Oliveira, D.; Borges, A.; Simões, M. Staphylococcus aureus Toxins and Their Molecular Activity in Infectious Diseases. Toxins 2018, 10, 252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shimaoka, M.; Yoh, M.; Takarada, Y.; Yamamoto, K.; Honda, T. Detection of the Gene for Toxic Shock Syndrome Toxin 1 in Staphylococcus aureus by Enzyme-Labelled Oligonucleotide Probes. J. Med. Microbiol. 1996, 44, 215–218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, M.; Liu, J.; Guo, Y.; Zhang, Z. Characterization of Virulence Factors and Genetic Background of Staphylococcus aureus Isolated from Peking University People’s Hospital between 2005 and 2009. Curr. Microbiol. 2010, 61, 435–443. [Google Scholar] [CrossRef]
- Ezeamagu, C.; Imanatue, I.; Dosunmu, M.; Odeseye, A.; Baysah, G.; Aina, D.; Odutayo, F.; Mensah-Agyei, G. Detection of Methicillin Resistant and Toxin-Associated Genes in Staphylococcus aureus. Beni-Suef Univ. J. Basic Appl. Sci. 2018, 7, 92–97. [Google Scholar] [CrossRef]
- Suaya, J.A.; Mera, R.M.; Cassidy, A.; O’Hara, P.; Amrine-Madsen, H.; Burstin, S.; Miller, L.G. Incidence and Cost of Hospitalizations Associated with Staphylococcus aureus Skin and Soft Tissue Infections in the United States from 2001 through 2009. BMC Infect. Dis. 2014, 14, 296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhen, X.; Lundborg, C.S.; Zhang, M.; Sun, X.; Li, Y.; Hu, X.; Gu, S.; Gu, Y.; Wei, J.; Dong, H. Clinical and Economic Impact of Methicillin-Resistant Staphylococcus aureus: A Multicentre Study in China. Sci. Rep. 2020, 10, 3900. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Egorov, A.M.; Ulyashova, M.M.; Rubtsova, M.Y. Bacterial Enzymes and Antibiotic Resistance. Acta Naturae 2018, 10, 33–48. [Google Scholar] [CrossRef] [Green Version]
- Varela, M.F.; Stephen, J.; Lekshmi, M.; Ojha, M.; Wenzel, N.; Sanford, L.M.; Hernandez, A.J.; Parvathi, A.; Kumar, S.H. Bacterial Resistance to Antimicrobial Agents. Antibiotics 2021, 10, 593. [Google Scholar] [CrossRef] [PubMed]
- Tackling Drug-Resistant Infections Globally: Final Report and Recommendations—The Review on Antimicrobial Resistance. Available online: https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf (accessed on 23 August 2021).
- Fleitas Martínez, O.; Cardoso, M.H.; Ribeiro, S.M.; Franco, O.L. Recent Advances in Anti-Virulence Therapeutic Strategies with a Focus on Dismantling Bacterial Membrane Microdomains, Toxin Neutralization, Quorum-Sensing Interference and Biofilm Inhibition. Front. Cell. Infect. Microbiol. 2019, 9, 74. [Google Scholar] [CrossRef]
- Kim, M.-K. Staphylococcus aureus Toxins: From Their Pathogenic Roles to Anti-Virulence Therapy Using Natural Products. Biotechnol. Bioprocess Eng. 2019, 24, 424–435. [Google Scholar] [CrossRef]
- Bennett, M.R.; Thomsen, I.P. Epidemiological and Clinical Evidence for the Role of Toxins in Staphylococcus aureus Human Disease. Toxins 2020, 12, 408. [Google Scholar] [CrossRef] [PubMed]
- Vlaeminck, J.; Raafat, D.; Surmann, K.; Timbermont, L.; Normann, N.; Sellman, B.; van Wamel, W.J.B.; Malhotra-Kumar, S. Exploring Virulence Factors and Alternative Therapies against Staphylococcus aureus Pneumonia. Toxins 2020, 12, 721. [Google Scholar] [CrossRef]
- Ford, C.A.; Hurford, I.M.; Cassat, J.E. Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review. Front. Microbiol. 2021, 11, 3568. [Google Scholar] [CrossRef]
- Divyakolu, S.; Chikkala, R.; Ratnakar, K.S.; Sritharan, V. Hemolysins of Staphylococcus aureus—An Update on Their Biology, Role in Pathogenesis and as Targets for Anti-Virulence Therapy. Adv. Infect. Dis. 2019, 9, 80–104. [Google Scholar] [CrossRef] [Green Version]
- Berube, B.J.; Wardenburg, J.B. Staphylococcus aureus α-Toxin: Nearly a Century of Intrigue. Toxins 2013, 5, 1140–1166. [Google Scholar] [CrossRef] [Green Version]
- Hernandez, S.L.; Nelson, M.; Sampedro, G.R.; Bagrodia, N.; Defnet, A.M.; Lec, B.; Emolo, J.; Kirschner, R.; Wu, L.; Biermann, H.; et al. Staphylococcus aureus Alpha Toxin Activates Notch in Vascular Cells. Angiogenesis 2019, 22, 197–209. [Google Scholar] [CrossRef]
- Bhakdi, S.; Tranum-Jensen, J. Alpha-Toxin of Staphylococcus aureus. Microbiol. Rev. 1991, 55, 733–751. [Google Scholar] [CrossRef]
- Pereira-Franchi, E.P.L.; Barreira, M.R.N.; de Costa, N.d.S.L.M.; Riboli, D.F.M.; Abraão, L.M.; Martins, K.B.; Victória, C.; da Cunha, M.d.L.R.d.S. Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus in the Brazilian Primary Health Care System. Trop. Med. Int. Health 2019, 24, 339–347. [Google Scholar] [CrossRef] [PubMed]
- Bubeck Wardenburg, J.; Palazzolo-Ballance, A.M.; Otto, M.; Schneewind, O.; DeLeo, F.R. Panton-Valentine Leukocidin Is Not a Virulence Determinant in Murine Models of Community-Associated Methicillin-Resistant Staphylococcus aureus Disease. J. Infect. Dis. 2008, 198, 1166–1170. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Crémieux, A.-C.; Saleh-Mghir, A.; Danel, C.; Couzon, F.; Dumitrescu, O.; Lilin, T.; Perronne, C.; Etienne, J.; Lina, G.; Vandenesch, F. α-Hemolysin, Not Panton-Valentine Leukocidin, Impacts Rabbit Mortality from Severe Sepsis with Methicillin-Resistant Staphylococcus aureus Osteomyelitis. J. Infect. Dis. 2014, 209, 1773–1780. [Google Scholar] [CrossRef] [Green Version]
- Montgomery, C.P.; Boyle-Vavra, S.; Adem, P.V.; Lee, J.C.; Husain, A.N.; Clasen, J.; Daum, R.S. Comparison of Virulence in Community-Associated Methicillin-Resistant Staphylococcus aureus Pulsotypes USA300 and USA400 in a Rat Model of Pneumonia. J. Infect. Dis. 2008, 198, 561–570. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Spaan, A.N.; van Strijp, J.A.G.; Torres, V.J. Leukocidins: Staphylococcal Bi-Component Pore-Forming Toxins Find Their Receptors. Nat. Rev. Microbiol. 2017, 15, 435–447. [Google Scholar] [CrossRef] [PubMed]
- Grumann, D.; Nübel, U.; Bröker, B.M. Staphylococcus aureus Toxins–Their Functions and Genetics. Infect. Genet. Evol. 2014, 21, 583–592. [Google Scholar] [CrossRef] [Green Version]
- Alonzo, F.; Kozhaya, L.; Rawlings, S.A.; Reyes-Robles, T.; DuMont, A.L.; Myszka, D.G.; Landau, N.R.; Unutmaz, D.; Torres, V.J. CCR5 Is a Receptor for Staphylococcus aureus Leukotoxin ED. Nature 2013, 493, 51–55. [Google Scholar] [CrossRef] [Green Version]
- Spaan, A.N.; Henry, T.; van Rooijen, W.J.M.; Perret, M.; Badiou, C.; Aerts, P.C.; Kemmink, J.; de Haas, C.J.C.; van Kessel, K.P.M.; Vandenesch, F.; et al. The Staphylococcal Toxin Panton-Valentine Leukocidin Targets Human C5a Receptors. Cell Host Microbe 2013, 13, 584–594. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- DuMont, A.L.; Yoong, P.; Day, C.J.; Alonzo, F.; McDonald, W.H.; Jennings, M.P.; Torres, V.J. Staphylococcus aureus LukAB Cytotoxin Kills Human Neutrophils by Targeting the CD11b Subunit of the Integrin Mac-1. Proc. Natl. Acad. Sci. USA 2013, 110, 10794–10799. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kaneko, J.; Kamio, Y. Bacterial Two-Component and Hetero-Heptameric Pore-Forming Cytolytic Toxins: Structures, Pore-Forming Mechanism, and Organization of the Genes. Biosci. Biotechnol. Biochem. 2004, 68, 981–1003. [Google Scholar] [CrossRef] [Green Version]
- Shallcross, L.J.; Fragaszy, E.; Johnson, A.M.; Hayward, A.C. The Role of the Panton-Valentine Leucocidin Toxin in Staphylococcal Disease: A Systematic Review and Meta-Analysis. Lancet Infect. Dis. 2013, 13, 43–54. [Google Scholar] [CrossRef] [Green Version]
- Otter, J.A.; French, G.L. Molecular Epidemiology of Community-Associated Meticillin-Resistant Staphylococcus aureus in Europe. Lancet Infect. Dis. 2010, 10, 227–239. [Google Scholar] [CrossRef]
- Mesrati, I.; Saïdani, M.; Ennigrou, S.; Zouari, B.; Ben Redjeb, S. Clinical Isolates of Pantone-Valentine Leucocidin- and Gamma-Haemolysin-Producing Staphylococcus aureus: Prevalence and Association with Clinical Infections. J. Hosp. Infect. 2010, 75, 265–268. [Google Scholar] [CrossRef] [PubMed]
- Otto, M. Phenol-Soluble Modulins. Int. J. Med. Microbiol. 2014, 304, 164–169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Peschel, A.; Otto, M. Phenol-Soluble Modulins and Staphylococcal Infection. Nat. Rev. Microbiol. 2013, 11, 667–673. [Google Scholar] [CrossRef] [PubMed]
- Cheung, G.Y.C.; Joo, H.-S.; Chatterjee, S.S.; Otto, M. Phenol-Soluble Modulins–Critical Determinants of Staphylococcal Virulence. FEMS Microbiol. Rev. 2014, 38, 698–719. [Google Scholar] [CrossRef] [PubMed]
- Baldry, M.; Bojer, M.S.; Najarzadeh, Z.; Vestergaard, M.; Meyer, R.L.; Otzen, D.E.; Ingmer, H. Phenol-Soluble Modulins Modulate Persister Cell Formation in Staphylococcus aureus. Front. Microbiol. 2020, 11, 573253. [Google Scholar] [CrossRef] [PubMed]
- Zaman, M.; Andreasen, M. Cross-Talk between Individual Phenol-Soluble Modulins in Staphylococcus aureus Biofilm Enables Rapid and Efficient Amyloid Formation. eLife 2020, 9, e59776. [Google Scholar] [CrossRef]
- Queck, S.Y.; Jameson-Lee, M.; Villaruz, A.E.; Bach, T.-H.L.; Khan, B.A.; Sturdevant, D.E.; Ricklefs, S.M.; Li, M.; Otto, M. RNAIII-Independent Target Gene Control by the Agr Quorum-Sensing System: Insight into the Evolution of Virulence Regulation in Staphylococcus aureus. Mol. Cell 2008, 32, 150–158. [Google Scholar] [CrossRef] [Green Version]
- Zapf, R.L.; Wiemels, R.E.; Keogh, R.A.; Holzschu, D.L.; Howell, K.M.; Trzeciak, E.; Caillet, A.R.; King, K.A.; Selhorst, S.A.; Naldrett, M.J.; et al. The Small RNA Teg41 Regulates Expression of the Alpha Phenol-Soluble Modulins and Is Required for Virulence in Staphylococcus aureus. MBio 2019, 10, e02484-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kretschmer, D.; Gleske, A.-K.; Rautenberg, M.; Wang, R.; Köberle, M.; Bohn, E.; Schöneberg, T.; Rabiet, M.-J.; Boulay, F.; Klebanoff, S.J.; et al. Human Formyl Peptide Receptor 2 Senses Highly Pathogenic Staphylococcus aureus. Cell Host Microbe 2010, 7, 463–473. [Google Scholar] [CrossRef] [Green Version]
- Schreiner, J.; Kretschmer, D.; Klenk, J.; Otto, M.; Bühring, H.-J.; Stevanovic, S.; Wang, J.M.; Beer-Hammer, S.; Peschel, A.; Autenrieth, S.E. Staphylococcus aureus Phenol-Soluble Modulin Peptides Modulate Dendritic Cell Functions and Increase In Vitro Priming of Regulatory T Cells. J. Immunol. 2013, 190, 3417–3426. [Google Scholar] [CrossRef] [Green Version]
- Wang, R.; Braughton, K.R.; Kretschmer, D.; Bach, T.-H.L.; Queck, S.Y.; Li, M.; Kennedy, A.D.; Dorward, D.W.; Klebanoff, S.J.; Peschel, A.; et al. Identification of Novel Cytolytic Peptides as Key Virulence Determinants for Community-Associated MRSA. Nat. Med. 2007, 13, 1510–1514. [Google Scholar] [CrossRef] [PubMed]
- Gonzalez, D.J.; Vuong, L.; Gonzalez, I.S.; Keller, N.; McGrosso, D.; Hwang, J.H.; Hung, J.; Zinkernagel, A.; Dixon, J.E.; Dorrestein, P.C.; et al. Phenol Soluble Modulin (PSM) Variants of Community-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) Captured Using Mass Spectrometry-Based Molecular Networking. Mol. Cell. Proteom. 2014, 13, 1262–1272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Davido, B.; Saleh-Mghir, A.; Laurent, F.; Danel, C.; Couzon, F.; Gatin, L.; Vandenesch, F.; Rasigade, J.-P.; Crémieux, A.-C. Phenol-Soluble Modulins Contribute to Early Sepsis Dissemination Not Late Local Usa300-Osteomyelitis Severity in Rabbits. PLoS ONE 2016, 11, e0157133. [Google Scholar] [CrossRef] [Green Version]
- Richardson, J.R.; Armbruster, N.S.; Günter, M.; Biljecki, M.; Klenk, J.; Heumos, S.; Autenrieth, S.E. PSM Peptides from Community-Associated Methicillin-Resistant Staphylococcus aureus Impair the Adaptive Immune Response via Modulation of Dendritic Cell Subsets in Vivo. Front. Immunol. 2019, 10, 995. [Google Scholar] [CrossRef]
- Czech, A.; Yamaguchi, T.; Bader, L.; Linder, S.; Kaminski, K.; Sugai, M.; Aepfelbacher, M. Prevalence of Rho-Inactivating Epidermal Cell Differentiation Inhibitor Toxins in Clinical Staphylococcus aureus Isolates. J. Infect. Dis. 2001, 184, 785–788. [Google Scholar] [CrossRef] [Green Version]
- Messad, N.; Landraud, L.; Canivet, B.; Lina, G.; Richard, J.-L.; Sotto, A.; Lavigne, J.-P.; Lemichez, E. Distribution of Edin in Staphylococcus aureus Isolated from Diabetic Foot Ulcers. Clin. Microbiol. Infect. 2013, 19, 875–880. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Boyer, L.; Doye, A.; Rolando, M.; Flatau, G.; Munro, P.; Gounon, P.; Clément, R.; Pulcini, C.; Popoff, M.R.; Mettouchi, A.; et al. Induction of Transient Macroapertures in Endothelial Cells through RhoA Inhibition by Staphylococcus aureus Factors. J. Cell Biol. 2006, 173, 809–819. [Google Scholar] [CrossRef] [PubMed]
- Aktories, K.; Lang, A.E.; Schwan, C.; Mannherz, H.G. Actin as Target for Modification by Bacterial Protein Toxins. FEBS J. 2011, 278, 4526–4543. [Google Scholar] [CrossRef]
- Jaffe, A.B.; Hall, A. Rho GTPases: Biochemistry and Biology. Annu. Rev. Cell Dev. Biol. 2005, 21, 247–269. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nusrat, A.; Giry, M.; Turner, J.R.; Colgan, S.P.; Parkos, C.A.; Carnes, D.; Lemichez, E.; Boquet, P.; Madara, J.L. Rho Protein Regulates Tight Junctions and Perijunctional Actin Organization in Polarized Epithelia. Proc. Natl. Acad. Sci. USA 1995, 92, 10629–10633. [Google Scholar] [CrossRef] [Green Version]
- Caron, E.; Hall, A. Identification of Two Distinct Mechanisms of Phagocytosis Controlled by Different Rho GTPases. Science 1998, 282, 1717–1721. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lemichez, E.; Lecuit, M.; Nassif, X.; Bourdoulous, S. Breaking the Wall: Targeting of the Endothelium by Pathogenic Bacteria. Nat. Rev. Microbiol. 2010, 8, 93–104. [Google Scholar] [CrossRef]
- Edwards, A.M.; Massey, R.C. How Does Staphylococcus aureus Escape the Bloodstream? Trends Microbiol. 2011, 19, 184–190. [Google Scholar] [CrossRef]
- Sugai, M.; Enomoto, T.; Hashimoto, K.; Matsumoto, K.; Matsuo, Y.; Ohgai, H.; Hong, Y.-M.; Inoue, S.; Yoshikawa, K.; Suginaka, H. A Novel Epidermal Cell Differentiation Inhibitor (EDIN): Purification and Characterization from Staphylococcus aureus. Biochem. Biophys. Res. Commun. 1990, 173, 92–98. [Google Scholar] [CrossRef]
- Yamaguchi, T.; Hayashi, T.; Takami, H.; Ohnishi, M.; Murata, T.; Nakayama, K.; Asakawa, K.; Ohara, M.; Komatsuzawa, H.; Sugai, M. Complete Nucleotide Sequence of a Staphylococcus aureus Exfoliative Toxin B Plasmid and Identification of a Novel ADP-Ribosyltransferase, EDIN-C. Infect. Immun. 2001, 69, 7760–7771. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yamaguchi, T.; Nishifuji, K.; Sasaki, M.; Fudaba, Y.; Aepfelbacher, M.; Takata, T.; Ohara, M.; Komatsuzawa, H.; Amagai, M.; Sugai, M. Identification of the Staphylococcus aureus Etd Pathogenicity Island Which Encodes a Novel Exfoliative Toxin, ETD, and EDIN-B. Infect. Immun. 2002, 70, 5835–5845. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Munro, P.; Benchetrit, M.; Nahori, M.-A.; Stefani, C.; Clément, R.; Michiels, J.-F.; Landraud, L.; Dussurget, O.; Lemichez, E. The Staphylococcus aureus Epidermal Cell Differentiation Inhibitor Toxin Promotes Formation of Infection Foci in a Mouse Model of Bacteremia. Infect. Immun. 2010, 78, 3404–3411. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Antri, K.; Rouzic, N.; Boubekri, I.; Dauwalder, O.; Beloufa, A.; Ziane, H.; Djennane, F.; Neggazi, M.; Benhabyles, B.; Bes, M.; et al. High prevalence of community and hospital acquired infections of methicillin-resistant Staphylococcus aureus containing Panton-Valentine leukocidin gene in Algiers. Pathol. Biol. 2010, 58, e15–e20. [Google Scholar] [CrossRef] [PubMed]
- Courjon, J.; Munro, P.; Benito, Y.; Visvikis, O.; Bouchiat, C.; Boyer, L.; Doye, A.; Lepidi, H.; Ghigo, E.; Lavigne, J.-P.; et al. EDIN-B Promotes the Translocation of Staphylococcus aureus to the Bloodstream in the Course of Pneumonia. Toxins 2015, 7, 4131–4142. [Google Scholar] [CrossRef] [Green Version]
- Pérez-Montarelo, D.; Viedma, E.; Larrosa, N.; Gómez-González, C.; Ruiz de Gopegui, E.; Muñoz-Gallego, I.; San Juan, R.; Fernández-Hidalgo, N.; Almirante, B.; Chaves, F. Molecular Epidemiology of Staphylococcus aureus Bacteremia: Association of Molecular Factors With the Source of Infection. Front. Microbiol. 2018, 9, 2210. [Google Scholar] [CrossRef] [PubMed]
- Bukowski, M.; Wladyka, B.; Dubin, G. Exfoliative Toxins of Staphylococcus aureus. Toxins 2010, 2, 1148–1165. [Google Scholar] [CrossRef] [Green Version]
- Stanley, J.R.; Amagai, M. Pemphigus, Bullous Impetigo, and the Staphylococcal Scalded-Skin Syndrome. N. Engl. J. Med. 2006, 355, 1800–1810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kato, F.; Kadomoto, N.; Iwamoto, Y.; Bunai, K.; Komatsuzawa, H.; Sugai, M. Regulatory Mechanism for Exfoliative Toxin Production in Staphylococcus aureus. Infect. Immun. 2011, 79, 1660–1670. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Eyre, R.W.; Stanley, J.R. Human Autoantibodies against a Desmosomal Protein Complex with a Calcium-Sensitive Epitope Are Characteristic of Pemphigus Foliaceus Patients. J. Exp. Med. 1987, 165, 1719–1724. [Google Scholar] [CrossRef] [Green Version]
- Hanakawa, Y.; Schechter, N.M.; Lin, C.; Garza, L.; Li, H.; Yamaguchi, T.; Fudaba, Y.; Nishifuji, K.; Sugai, M.; Amagai, M.; et al. Molecular Mechanisms of Blister Formation in Bullous Impetigo and Staphylococcal Scalded Skin Syndrome. J. Clin. Investig. 2002, 110, 53–60. [Google Scholar] [CrossRef] [PubMed]
- Nishifuji, K.; Sugai, M.; Amagai, M. Staphylococcal Exfoliative Toxins: “Molecular Scissors” of Bacteria That Attack the Cutaneous Defense Barrier in Mammals. J. Dermatol. Sci. 2008, 49, 21–31. [Google Scholar] [CrossRef] [PubMed]
- Sila, J.; Sauer, P.; Kolar, M. Comparison of the Prevalence of Genes Coding for Enterotoxins, Exfoliatins, Panton-Valentine Leukocidin and Tsst-1 between Methicillin-Resistant and Methicillin-Susceptible Isolates of Staphylococcus aureus at the University Hospital in Olomouc. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czechoslov. 2009, 153, 215–218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mégevand, C.; Gervaix, A.; Heininger, U.; Berger, C.; Aebi, C.; Vaudaux, B.; Kind, C.; Gnehm, H.-P.; Hitzler, M.; Renzi, G.; et al. Molecular Epidemiology of the Nasal Colonization by Methicillin-Susceptible Staphylococcus aureus in Swiss Children. Clin. Microbiol. Infect. 2010, 16, 1414–1420. [Google Scholar] [CrossRef]
- Yamaguchi, T.; Yokota, Y.; Terajima, J.; Hayashi, T.; Aepfelbacher, M.; Ohara, M.; Komatsuzawa, H.; Watanabe, H.; Sugai, M. Clonal Association of Staphylococcus aureus Causing Bullous Impetigo and the Emergence of New Methicillin-Resistant Clonal Groups in Kansai District in Japan. J. Infect. Dis. 2002, 185, 1511–1516. [Google Scholar] [CrossRef] [Green Version]
- Noguchi, N.; Nakaminami, H.; Nishijima, S.; Kurokawa, I.; So, H.; Sasatsu, M. Antimicrobial Agent of Susceptibilities and Antiseptic Resistance Gene Distribution among Methicillin-Resistant Staphylococcus aureus Isolates from Patients with Impetigo and Staphylococcal Scalded Skin Syndrome. J. Clin. Microbiol. 2006, 44, 2119–2125. [Google Scholar] [CrossRef] [Green Version]
- Wieczorek, M.; Abualrous, E.T.; Sticht, J.; Álvaro-Benito, M.; Stolzenberg, S.; Noé, F.; Freund, C. Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Front. Immunol. 2017, 8, 292. [Google Scholar] [CrossRef] [Green Version]
- Fraser, J.D.; Proft, T. The Bacterial Superantigen and Superantigen-like Proteins. Immunol. Rev. 2008, 225, 226–243. [Google Scholar] [CrossRef]
- Lina, G.; Bohach, G.A.; Nair, S.P.; Hiramatsu, K.; Jouvin-Marche, E.; Mariuzza, R. Standard Nomenclature for the Superantigens Expressed by Staphylococcus. J. Infect. Dis. 2004, 189, 2334–2336. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hennekinne, J.-A.; De Buyser, M.-L.; Dragacci, S. Staphylococcus aureus and Its Food Poisoning Toxins: Characterization and Outbreak Investigation. FEMS Microbiol. Rev. 2012, 36, 815–836. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Otto, M. Staphylococcus aureus Toxins. Curr. Opin. Microbiol. 2014, 17, 32–37. [Google Scholar] [CrossRef] [Green Version]
- Hu, D.-L.; Li, S.; Fang, R.; Ono, H.K. Update on Molecular Diversity and Multipathogenicity of Staphylococcal Superantigen Toxins. Anim. Dis. 2021, 1, 7. [Google Scholar] [CrossRef]
- Kong, C.; Neoh, H.; Nathan, S. Targeting Staphylococcus aureus Toxins: A Potential Form of Anti-Virulence Therapy. Toxins 2016, 8, 72. [Google Scholar] [CrossRef] [Green Version]
- Fisher, E.L.; Otto, M.; Cheung, G.Y.C. Basis of Virulence in Enterotoxin-Mediated Staphylococcal Food Poisoning. Front. Microbiol. 2018, 9, 436. [Google Scholar] [CrossRef] [PubMed]
- Uchiyama, T.; Araake, M.; Yan, X.J.; Miyanaga, Y.; Igarashi, H. Involvement of HLA Class II Molecules in Acquisition of Staphylococcal Enterotoxin A-Binding Activity and Accessory Cell Activity in Activation of Human T Cells by Related Toxins in Vascular Endothelial Cells. Clin. Exp. Immunol. 1992, 87, 322–328. [Google Scholar] [CrossRef]
- Pezato, R.; Świerczyńska-Krępa, M.; Niżankowska-Mogilnicka, E.; Derycke, L.; Bachert, C.; Pérez-Novo, C.A. Role of Imbalance of Eicosanoid Pathways and Staphylococcal Superantigens in Chronic Rhinosinusitis. Allergy 2012, 67, 1347–1356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pinchuk, I.V.; Beswick, E.J.; Reyes, V.E. Staphylococcal Enterotoxins. Toxins 2010, 2, 2177–2197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Salgado-Pabón, W.; Breshears, L.; Spaulding, A.R.; Merriman, J.A.; Stach, C.S.; Horswill, A.R.; Peterson, M.L.; Schlievert, P.M. Superantigens Are Critical for Staphylococcus aureus Infective Endocarditis, Sepsis, and Acute Kidney Injury. MBio 2013, 4, e00494-13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stach, C.S.; Herrera, A.; Schlievert, P.M. Staphylococcal Superantigens Interact with Multiple Host Receptors to Cause Serious Diseases. Immunol. Res. 2014, 59, 177–181. [Google Scholar] [CrossRef] [PubMed]
- McCormick, J.K.; Yarwood, J.M.; Schlievert, P.M. Toxic Shock Syndrome and Bacterial Superantigens: An Update. Annu. Rev. Microbiol. 2001, 55, 77–104. [Google Scholar] [CrossRef]
- Adhikari, R.P.; Ajao, A.O.; Aman, M.J.; Karauzum, H.; Sarwar, J.; Lydecker, A.D.; Johnson, J.K.; Nguyen, C.; Chen, W.H.; Roghmann, M.-C. Lower Antibody Levels to Staphylococcus aureus Exotoxins Are Associated With Sepsis in Hospitalized Adults With Invasive S. aureus Infections. J. Infect. Dis. 2012, 206, 915–923. [Google Scholar] [CrossRef] [PubMed]
- Sharma-Kuinkel, B.K.; Tkaczyk, C.; Bonnell, J.; Yu, L.; Tovchigrechko, A.; Tabor, D.E.; Park, L.P.; Ruffin, F.; Esser, M.T.; Sellman, B.R.; et al. Associations of Pathogen-Specific and Host-Specific Characteristics with Disease Outcome in Patients with Staphylococcus aureus Bacteremic Pneumonia. Clin. Transl. Immunol. 2019, 8, e01070. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gillet, Y.; Issartel, B.; Vanhems, P.; Fournet, J.-C.; Lina, G.; Bes, M.; Vandenesch, F.; Piémont, Y.; Brousse, N.; Floret, D.; et al. Association between Staphylococcus aureus Strains Carrying Gene for Panton-Valentine Leukocidin and Highly Lethal Necrotising Pneumonia in Young Immunocompetent Patients. Lancet 2002, 359, 753–759. [Google Scholar] [CrossRef]
- Verdon, J.; Girardin, N.; Lacombe, C.; Berjeaud, J.-M.; Héchard, Y. Delta-Hemolysin, an Update on a Membrane-Interacting Peptide. Peptides 2009, 30, 817–823. [Google Scholar] [CrossRef]
- Surewaard, B.G.J.; de Haas, C.J.C.; Vervoort, F.; Rigby, K.M.; DeLeo, F.R.; Otto, M.; van Strijp, J.A.G.; Nijland, R. Staphylococcal Alpha-Phenol Soluble Modulins Contribute to Neutrophil Lysis after Phagocytosis. Cell. Microbiol. 2013, 15, 1427–1437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mishra, A.K.; Yadav, P.; Mishra, A. A Systemic Review on Staphylococcal Scalded Skin Syndrome (SSSS): A Rare and Critical Disease of Neonates. Open Microbiol. J. 2016, 10, 150. [Google Scholar] [CrossRef] [Green Version]
- Wilke, G.A.; Bubeck Wardenburg, J. Role of a Disintegrin and Metalloprotease 10 in Staphylococcus aureus Alpha-Hemolysin-Mediated Cellular Injury. Proc. Natl. Acad. Sci. USA 2010, 107, 13473–13478. [Google Scholar] [CrossRef] [Green Version]
- Foletti, D.; Strop, P.; Shaughnessy, L.; Hasa-Moreno, A.; Casas, M.G.; Russell, M.; Bee, C.; Wu, S.; Pham, A.; Zeng, Z.; et al. Mechanism of Action and in Vivo Efficacy of a Human-Derived Antibody against Staphylococcus aureus α-Hemolysin. J. Mol. Biol. 2013, 425, 1641–1654. [Google Scholar] [CrossRef]
- Oganesyan, V.; Peng, L.; Damschroder, M.M.; Cheng, L.; Sadowska, A.; Tkaczyk, C.; Sellman, B.R.; Wu, H.; Dall’Acqua, W.F. Mechanisms of Neutralization of a Human Anti-α-Toxin Antibody. J. Biol. Chem. 2014, 289, 29874–29880. [Google Scholar] [CrossRef] [Green Version]
- Le, V.T.M.; Tkaczyk, C.; Chau, S.; Rao, R.L.; Dip, E.C.; Pereira-Franchi, E.P.; Cheng, L.; Lee, S.; Koelkebeck, H.; Hilliard, J.J.; et al. Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections. Antimicrob. Agents Chemother. 2016, 60, 5640–5648. [Google Scholar] [CrossRef] [Green Version]
- Ortines, R.V.; Liu, H.; Cheng, L.I.; Cohen, T.S.; Lawlor, H.; Gami, A.; Wang, Y.; Dillen, C.A.; Archer, N.K.; Miller, R.J.; et al. Neutralizing Alpha-Toxin Accelerates Healing of Staphylococcus aureus-Infected Wounds in Nondiabetic and Diabetic Mice. Antimicrob. Agents Chemother. 2018, 62, e02288-17. [Google Scholar] [CrossRef] [Green Version]
- Surewaard, B.G.J.; Thanabalasuriar, A.; Zeng, Z.; Tkaczyk, C.; Cohen, T.S.; Bardoel, B.W.; Jorch, S.K.; Deppermann, C.; Bubeck Wardenburg, J.; Davis, R.P.; et al. α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis. Cell Host Microbe 2018, 24, 271–284.e3. [Google Scholar] [CrossRef] [PubMed]
- Yu, X.-Q.; Robbie, G.J.; Wu, Y.; Esser, M.T.; Jensen, K.; Schwartz, H.I.; Bellamy, T.; Hernandez-Illas, M.; Jafri, H.S. Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults. Antimicrob. Agents Chemother. 2017, 61, e01020-16. [Google Scholar] [CrossRef] [Green Version]
- François, B.; Jafri, H.S.; Chastre, J.; Sánchez-García, M.; Eggimann, P.; Dequin, P.-F.; Huberlant, V.; Viña Soria, L.; Boulain, T.; Bretonnière, C.; et al. Efficacy and Safety of Suvratoxumab for Prevention of Staphylococcus aureus Ventilator-Associated Pneumonia (SAATELLITE): A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 2 Pilot Trial. Lancet Infect. Dis. 2021, 21, 1313–1323. [Google Scholar] [CrossRef]
- François, B.; Mercier, E.; Gonzalez, C.; Asehnoune, K.; Nseir, S.; Fiancette, M.; Desachy, A.; Plantefève, G.; Meziani, F.; de Lame, P.-A.; et al. Safety and Tolerability of a Single Administration of AR-301, a Human Monoclonal Antibody, in ICU Patients with Severe Pneumonia Caused by Staphylococcus aureus: First-in-Human Trial. Intensive Care Med. 2018, 44, 1787–1796. [Google Scholar] [CrossRef]
- Magyarics, Z.; Leslie, F.; Bartko, J.; Rouha, H.; Luperchio, S.; Schörgenhofer, C.; Schwameis, M.; Derhaschnig, U.; Lagler, H.; Stiebellehner, L.; et al. Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study of the Penetration of a Monoclonal Antibody Combination (ASN100) Targeting Staphylococcus aureus Cytotoxins in the Lung Epithelial Lining Fluid of Healthy Volunteers. Antimicrob. Agents Chemother. 2019, 63, e00350-19. [Google Scholar] [CrossRef] [Green Version]
- Ruzin, A.; Yu, L.; Barraud, O.; François, B.; Sánchez Garcia, M.; Eggimann, P.; Dequin, P.-F.; Laterre, P.-F.; Huberlant, V.; Viña, L.; et al. 2160. Performance of the Cepheid Rapid PCR Test for Patient Screening and Association with Efficacy of Suvratoxumab, A Novel Anti-Staphylococcus aureus Monoclonal Antibody, During the Phase 2 SAATELLITE Study. Open Forum Infect. Dis. 2019, 6, S733. [Google Scholar] [CrossRef]
- Vandenesch, F.; Naimi, T.; Enright, M.C.; Lina, G.; Nimmo, G.R.; Heffernan, H.; Liassine, N.; Bes, M.; Greenland, T.; Reverdy, M.-E.; et al. Community-Acquired Methicillin-Resistant Staphylococcus aureus Carrying Panton-Valentine Leukocidin Genes: Worldwide Emergence. Emerg. Infect. Dis. 2003, 9, 978–984. [Google Scholar] [CrossRef] [PubMed]
- Diep, B.A.; Otto, M. The Role of Virulence Determinants in Community-Associated MRSA Pathogenesis. Trends Microbiol. 2008, 16, 361–369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hermos, C.R.; Yoong, P.; Pier, G.B. High Levels of Antibody to Panton-Valentine Leukocidin Are Not Associated with Resistance to Staphylococcus aureus-Associated Skin and Soft-Tissue Infection. Clin. Infect. Dis. 2010, 51, 1138–1146. [Google Scholar] [CrossRef] [Green Version]
- Gauduchon, V.; Cozon, G.; Vandenesch, F.; Genestier, A.-L.; Eyssade, N.; Peyrol, S.; Etienne, J.; Lina, G. Neutralization of Staphylococcus aureus Panton Valentine Leukocidin by Intravenous Immunoglobulin In Vitro. J. Infect. Dis. 2004, 189, 346–353. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mairpady Shambat, S.; Chen, P.; Nguyen Hoang, A.T.; Bergsten, H.; Vandenesch, F.; Siemens, N.; Lina, G.; Monk, I.R.; Foster, T.J.; Arakere, G.; et al. Modelling Staphylococcal Pneumonia in a Human 3D Lung Tissue Model System Delineates Toxin-Mediated Pathology. Dis. Model. Mech. 2015, 8, 1413–1425. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rouzic, N.; Janvier, F.; Libert, N.; Javouhey, E.; Lina, G.; Nizou, J.-Y.; Pasquier, P.; Stamm, D.; Brinquin, L.; Pelletier, C.; et al. Prompt and Successful Toxin-Targeting Treatment of Three Patients with Necrotizing Pneumonia Due to Staphylococcus aureus Strains Carrying the Panton-Valentine Leukocidin Genes. J. Clin. Microbiol. 2010, 48, 1952–1955. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Laventie, B.-J.; Rademaker, H.J.; Saleh, M.; de Boer, E.; Janssens, R.; Bourcier, T.; Subilia, A.; Marcellin, L.; van Haperen, R.; Lebbink, J.H.G.; et al. Heavy Chain-Only Antibodies and Tetravalent Bispecific Antibody Neutralizing Staphylococcus aureus Leukotoxins. Proc. Natl. Acad. Sci. USA 2011, 108, 16404–16409. [Google Scholar] [CrossRef] [Green Version]
- Aman, M.J. Superantigens of a Superbug: Major Culprits of Staphylococcus aureus Disease? Virulence 2017, 8, 607–610. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Drozdowski, B.; Zhou, Y.; Kline, B.; Spidel, J.; Chan, Y.Y.; Albone, E.; Turchin, H.; Chao, Q.; Henry, M.; Balogach, J.; et al. Generation and Characterization of High Affinity Human Monoclonal Antibodies That Neutralize Staphylococcal Enterotoxin B. J. Immune Based Ther. Vaccines 2010, 8, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Varshney, A.K.; Wang, X.; Scharff, M.D.; MacIntyre, J.; Zollner, R.S.; Kovalenko, O.V.; Martinez, L.R.; Byrne, F.R.; Fries, B.C. Staphylococcal Enterotoxin B-Specific Monoclonal Antibody 20B1 Successfully Treats Diverse Staphylococcus aureus Infections. J. Infect. Dis. 2013, 208, 2058–2066. [Google Scholar] [CrossRef] [Green Version]
- Fang, R.H.; Luk, B.T.; Hu, C.-M.J.; Zhang, L. Engineered Nanoparticles Mimicking Cell Membranes for Toxin Neutralization. Adv. Drug Deliv. Rev. 2015, 90, 69–80. [Google Scholar] [CrossRef] [Green Version]
- Henry, B.D.; Neill, D.R.; Becker, K.A.; Gore, S.; Bricio-Moreno, L.; Ziobro, R.; Edwards, M.J.; Mühlemann, K.; Steinmann, J.; Kleuser, B.; et al. Engineered Liposomes Sequester Bacterial Exotoxins and Protect from Severe Invasive Infections in Mice. Nat. Biotechnol. 2015, 33, 81–88. [Google Scholar] [CrossRef] [Green Version]
- Wolfmeier, H.; Mansour, S.C.; Liu, L.T.; Pletzer, D.; Draeger, A.; Babiychuk, E.B.; Hancock, R.E.W. Liposomal Therapy Attenuates Dermonecrosis Induced by Community-Associated Methicillin-Resistant Staphylococcus aureus by Targeting α-Type Phenol-Soluble Modulins and α-Hemolysin. EBioMedicine 2018, 33, 211–217. [Google Scholar] [CrossRef]
- Keller, M.D.; Ching, K.L.; Liang, F.-X.; Dhabaria, A.; Tam, K.; Ueberheide, B.M.; Unutmaz, D.; Torres, V.J.; Cadwell, K. Decoy Exosomes Provide Protection against Bacterial Toxins. Nature 2020, 579, 260–264. [Google Scholar] [CrossRef]
- Chen, Y.; Chen, M.; Zhang, Y.; Lee, J.H.; Escajadillo, T.; Gong, H.; Fang, R.H.; Gao, W.; Nizet, V.; Zhang, L. Broad-Spectrum Neutralization of Pore-Forming Toxins with Human Erythrocyte Membrane-Coated Nanosponges. Adv. Healthc. Mater. 2018, 7, e1701366. [Google Scholar] [CrossRef] [PubMed]
- Wei, X.; Gao, J.; Wang, F.; Ying, M.; Angsantikul, P.; Kroll, A.V.; Zhou, J.; Gao, W.; Lu, W.; Fang, R.H.; et al. In Situ Capture of Bacterial Toxins for Antivirulence Vaccination. Adv. Mater. 2017, 29, 1701644. [Google Scholar] [CrossRef] [PubMed]
- Yarwood, J.M.; Bartels, D.J.; Volper, E.M.; Greenberg, E.P. Quorum Sensing in Staphylococcus aureus Biofilms. J. Bacteriol. 2004, 186, 1838–1850. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cheung, G.Y.C.; Wang, R.; Khan, B.A.; Sturdevant, D.E.; Otto, M. Role of the Accessory Gene Regulator Agr in Community-Associated Methicillin-Resistant Staphylococcus aureus Pathogenesis. Infect. Immun. 2011, 79, 1927–1935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Novick, R.P.; Ross, H.F.; Projan, S.J.; Kornblum, J.; Kreiswirth, B.; Moghazeh, S. Synthesis of Staphylococcal Virulence Factors Is Controlled by a Regulatory RNA Molecule. EMBO J. 1993, 12, 3967–3975. [Google Scholar] [CrossRef] [PubMed]
- Balaban, N.; Collins, L.V.; Cullor, J.S.; Hume, E.B.; Medina-Acosta, E.; Vieira da Motta, O.; O’Callaghan, R.; Rossitto, P.V.; Shirtliff, M.E.; Serafim da Silveira, L.; et al. Prevention of Diseases Caused by Staphylococcus aureus Using the Peptide RIP. Peptides 2000, 21, 1301–1311. [Google Scholar] [CrossRef]
- Gov, Y.; Bitler, A.; Dell’Acqua, G.; Torres, J.V.; Balaban, N. RNAIII Inhibiting Peptide (RIP), a Global Inhibitor of Staphylococcus aureus Pathogenesis: Structure and Function Analysis. Peptides 2001, 22, 1609–1620. [Google Scholar] [CrossRef]
- Vieira-da-Motta, O.; Damasceno Ribeiro, P.; Dias da Silva, W.; Medina-Acosta, E. RNAIII Inhibiting Peptide (RIP) Inhibits Agr-Regulated Toxin Production. Peptides 2001, 22, 1621–1627. [Google Scholar] [CrossRef]
- Ma, B.; Zhou, Y.; Li, M.; Yu, Q.; Xue, X.; Li, Z.; Da, F.; Hou, Z.; Luo, X. RIP-V Improves Murine Survival in a Sepsis Model by down-Regulating RNAIII Expression and α-Hemolysin Release of Methicillin-Resistant Staphylococcus aureus. Pharmazie 2015, 70, 81–87. [Google Scholar]
- 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]
- 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] [PubMed] [Green Version]
- Zhou, Y.; Niu, C.; Ma, B.; Xue, X.; Li, Z.; Chen, Z.; Li, F.; Zhou, S.; Luo, X.; Hou, Z. Inhibiting PSMα-Induced Neutrophil Necroptosis Protects Mice with MRSA Pneumonia by Blocking the Agr System. Cell Death Dis. 2018, 9, 362. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huan, Y.; Kong, Q.; Mou, H.; Yi, H. Antimicrobial Peptides: Classification, Design, Application and Research Progress in Multiple Fields. Front. Microbiol. 2020, 11, 2559. [Google Scholar] [CrossRef] [PubMed]
- Kudryashova, E.; Seveau, S.M.; Kudryashov, D.S. Targeting and Inactivation of Bacterial Toxins by Human Defensins. Biol. Chem. 2017, 398, 1069–1085. [Google Scholar] [CrossRef] [PubMed]
- Patrulea, V.; Borchard, G.; Jordan, O. An Update on Antimicrobial Peptides (AMPs) and Their Delivery Strategies for Wound Infections. Pharmaceutics 2020, 12, 840. [Google Scholar] [CrossRef]
- Lehrer, R.I.; Lu, W. α-Defensins in Human Innate Immunity. Immunol. Rev. 2012, 245, 84–112. [Google Scholar] [CrossRef] [PubMed]
- Lillard, J.W.; Boyaka, P.N.; Chertov, O.; Oppenheim, J.J.; McGhee, J.R. Mechanisms for Induction of Acquired Host Immunity by Neutrophil Peptide Defensins. Proc. Natl. Acad. Sci. USA 1999, 96, 651–656. [Google Scholar] [CrossRef] [Green Version]
- Diep, B.A.; Chan, L.; Tattevin, P.; Kajikawa, O.; Martin, T.R.; Basuino, L.; Mai, T.T.; Marbach, H.; Braughton, K.R.; Whitney, A.R.; et al. Polymorphonuclear Leukocytes Mediate Staphylococcus aureus Panton-Valentine Leukocidin-Induced Lung Inflammation and Injury. Proc. Natl. Acad. Sci. USA 2010, 107, 5587–5592. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cardot-Martin, E.; Casalegno, J.S.; Badiou, C.; Dauwalder, O.; Keller, D.; Prévost, G.; Rieg, S.; Kern, W.V.; Cuerq, C.; Etienne, J.; et al. α-Defensins Partially Protect Human Neutrophils against Panton-Valentine Leukocidin Produced by Staphylococcus aureus. Lett. Appl. Microbiol. 2015, 61, 158–164. [Google Scholar] [CrossRef]
- Karginov, V.A.; Nestorovich, E.M.; Schmidtmann, F.; Robinson, T.M.; Yohannes, A.; Fahmi, N.E.; Bezrukov, S.M.; Hecht, S.M. Inhibition of S. aureus α-Hemolysin and B. anthracis Lethal Toxin by β-Cyclodextrin Derivatives. Bioorg. Med. Chem. 2007, 15, 5424–5431. [Google Scholar] [CrossRef] [Green Version]
- Dong, J.; Qiu, J.; Wang, J.; Li, H.; Dai, X.; Zhang, Y.; Wang, X.; Tan, W.; Niu, X.; Deng, X.; et al. Apigenin Alleviates the Symptoms of Staphylococcus aureus Pneumonia by Inhibiting the Production of Alpha-Hemolysin. FEMS Microbiol. Lett. 2013, 338, 124–131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jiang, L.; Yi, T.; Shen, Z.; Teng, Z.; Wang, J. Aloe-Emodin Attenuates Staphylococcus aureus Pathogenicity by Interfering with the Oligomerization of α-Toxin. Front. Cell. Infect. Microbiol. 2019, 9, 157. [Google Scholar] [CrossRef] [PubMed]
- Wang, J.; Zhou, X.; Liu, S.; Li, G.; Shi, L.; Dong, J.; Li, W.; Deng, X.; Niu, X. Morin Hydrate Attenuates Staphylococcus aureus Virulence by Inhibiting the Self-Assembly of α-Hemolysin. J. Appl. Microbiol. 2015, 118, 753–763. [Google Scholar] [CrossRef]
- Dong, J.; Qiu, J.; Zhang, Y.; Lu, C.; Dai, X.; Wang, J.; Li, H.; Wang, X.; Tan, W.; Luo, M.; et al. Oroxylin A Inhibits Hemolysis via Hindering the Self-Assembly of α-Hemolysin Heptameric Transmembrane Pore. PLoS Comput. Biol. 2013, 9, e1002869. [Google Scholar] [CrossRef]
- Qiu, J.; Wang, D.; Zhang, Y.; Dong, J.; Wang, J.; Niu, X. Molecular Modeling Reveals the Novel Inhibition Mechanism and Binding Mode of Three Natural Compounds to Staphylococcal α-Hemolysin. PLoS ONE 2013, 8, e80197. [Google Scholar] [CrossRef]
- Friedman, M.; Rasooly, R.; Do, P.M.; Henika, P.R. The Olive Compound 4-Hydroxytyrosol Inactivates Staphylococcus aureus Bacteria and Staphylococcal Enterotoxin A (SEA). J. Food Sci. 2011, 76, M558–M563. [Google Scholar] [CrossRef] [PubMed]
- Mansson, M.; Nielsen, A.; Kjærulff, L.; Gotfredsen, C.H.; Wietz, M.; Ingmer, H.; Gram, L.; Larsen, T.O. Inhibition of Virulence Gene Expression in Staphylococcus aureus by Novel Depsipeptides from a Marine Photobacterium. Mar. Drugs 2011, 9, 2537–2552. [Google Scholar] [CrossRef] [Green Version]
- Nielsen, A.; Månsson, M.; Bojer, M.S.; Gram, L.; Larsen, T.O.; Novick, R.P.; Frees, D.; Frøkiær, H.; Ingmer, H. Solonamide B Inhibits Quorum Sensing and Reduces Staphylococcus aureus Mediated Killing of Human Neutrophils. PLoS ONE 2014, 9, e84992. [Google Scholar] [CrossRef] [Green Version]
- Baldry, M.; Kitir, B.; Frøkiær, H.; Christensen, S.B.; Taverne, N.; Meijerink, M.; Franzyk, H.; Olsen, C.A.; Wells, J.M.; Ingmer, H. The Agr Inhibitors Solonamide B and Analogues Alter Immune Responses to Staphylococcus aureus but Do Not Exhibit Adverse Effects on Immune Cell Functions. PLoS ONE 2016, 11, e0145618. [Google Scholar] [CrossRef] [PubMed]
- Baldry, M.; Nakamura, Y.; Nakagawa, S.; Frees, D.; Matsue, H.; Núñez, G.; Ingmer, H. Application of an Agr-Specific Antivirulence Compound as Therapy for Staphylococcus aureus-Induced Inflammatory Skin Disease. J. Infect. Dis. 2018, 218, 1009–1013. [Google Scholar] [CrossRef]
- Wang, J.; Qiu, J.; Dong, J.; Li, H.; Luo, M.; Dai, X.; Zhang, Y.; Leng, B.; Niu, X.; Zhao, S.; et al. Chrysin Protects Mice from Staphylococcus aureus Pneumonia. J. Appl. Microbiol. 2011, 111, 1551–1558. [Google Scholar] [CrossRef]
- Tang, F.; Li, W.-H.; Zhou, X.; Liu, Y.-H.; Li, Z.; Tang, Y.-S.; Kou, X.; Wang, S.-D.; Bao, M.; Qu, L.-D.; et al. Puerarin Protects against Staphylococcus aureus-Induced Injury of Human Alveolar Epithelial A549 Cells via Downregulating Alpha-Hemolysin Secretion. Microb. Drug Resist. 2014, 20, 357–363. [Google Scholar] [CrossRef] [PubMed]
- Jiang, L.; Li, H.; Wang, L.; Song, Z.; Shi, L.; Li, W.; Deng, X.; Wang, J. Isorhamnetin Attenuates Staphylococcus aureus-Induced Lung Cell Injury by Inhibiting Alpha-Hemolysin Expression. J. Microbiol. Biotechnol. 2016, 26, 596–602. [Google Scholar] [CrossRef] [Green Version]
- Nabavi, S.F.; Braidy, N.; Habtemariam, S.; Orhan, I.E.; Daglia, M.; Manayi, A.; Gortzi, O.; Nabavi, S.M. Neuroprotective Effects of Chrysin: From Chemistry to Medicine. Neurochem. Int. 2015, 90, 224–231. [Google Scholar] [CrossRef]
- Zhou, Y.-X.; Zhang, H.; Peng, C. Puerarin: A Review of Pharmacological Effects. Phytother. Res. PTR 2014, 28, 961–975. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Wang, J.-F.; Dong, J.; Wei, J.-Y.; Wang, Y.-N.; Dai, X.-H.; Wang, X.; Luo, M.-J.; Tan, W.; Deng, X.-M.; et al. Inhibition of α-Toxin Production by Subinhibitory Concentrations of Naringenin Controls Staphylococcus aureus Pneumonia. Fitoterapia 2013, 86, 92–99. [Google Scholar] [CrossRef] [PubMed]
- Salehi, B.; Fokou, P.V.T.; Sharifi-Rad, M.; Zucca, P.; Pezzani, R.; Martins, N.; Sharifi-Rad, J. The Therapeutic Potential of Naringenin: A Review of Clinical Trials. Pharmaceuticals 2019, 12, 11. [Google Scholar] [CrossRef] [Green Version]
- Quave, C.L.; Plano, L.R.W.; Bennett, B.C. Quorum Sensing Inhibitors of Staphylococcus aureus from Italian Medicinal Plants. Planta Med. 2011, 77, 188–195. [Google Scholar] [CrossRef] [Green Version]
- Muhs, A.; Lyles, J.T.; Parlet, C.P.; Nelson, K.; Kavanaugh, J.S.; Horswill, A.R.; Quave, C.L. Virulence Inhibitors from Brazilian Peppertree Block Quorum Sensing and Abate Dermonecrosis in Skin Infection Models. Sci. Rep. 2017, 7, 42275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Todd, D.A.; Parlet, C.P.; Crosby, H.A.; Malone, C.L.; Heilmann, K.P.; Horswill, A.R.; Cech, N.B. Signal Biosynthesis Inhibition with Ambuic Acid as a Strategy To Target Antibiotic-Resistant Infections. Antimicrob. Agents Chemother. 2017, 61, e00263-17. [Google Scholar] [CrossRef] [Green Version]
- Geisinger, E.; Muir, T.W.; Novick, R.P. Agr Receptor Mutants Reveal Distinct Modes of Inhibition by Staphylococcal Autoinducing Peptides. Proc. Natl. Acad. Sci. USA 2009, 106, 1216–1221. [Google Scholar] [CrossRef] [Green Version]
- Malachowa, N.; Kobayashi, S.D.; Braughton, K.R.; DeLeo, F.R. Mouse Model of Staphylococcus aureus Skin Infection. In Mouse Models of Innate Immunity; Humana Press: Totowa, NJ, USA, 2013; Volume 1031, pp. 109–116. [Google Scholar] [CrossRef]
- Menzies, B.E.; Kernodle, D.S. Site-Directed Mutagenesis of the Alpha-Toxin Gene of Staphylococcus aureus: Role of Histidines in Toxin Activity in Vitro and in a Murine Model. Infect. Immun. 1994, 62, 1843–1847. [Google Scholar] [CrossRef] [Green Version]
- Bubeck Wardenburg, J.; Schneewind, O. Vaccine Protection against Staphylococcus aureus Pneumonia. J. Exp. Med. 2008, 205, 287–294. [Google Scholar] [CrossRef]
- Karauzum, H.; Venkatasubramaniam, A.; Adhikari, R.P.; Kort, T.; Holtsberg, F.W.; Mukherjee, I.; Mednikov, M.; Ortines, R.; Nguyen, N.T.Q.; Doan, T.M.N.; et al. IBT-V02: A Multicomponent Toxoid Vaccine Protects Against Primary and Secondary Skin Infections Caused by Staphylococcus aureus. Front. Immunol. 2021, 12, 624310. [Google Scholar] [CrossRef]
- Brown, E.L.; Dumitrescu, O.; Thomas, D.; Badiou, C.; Koers, E.M.; Choudhury, P.; Vazquez, V.; Etienne, J.; Lina, G.; Vandenesch, F.; et al. The Panton-Valentine Leukocidin Vaccine Protects Mice against Lung and Skin Infections Caused by Staphylococcus aureus USA300. Clin. Microbiol. Infect. 2009, 15, 156–164. [Google Scholar] [CrossRef] [Green Version]
- Karauzum, H.; Adhikari, R.P.; Sarwar, J.; Devi, V.S.; Abaandou, L.; Haudenschild, C.; Mahmoudieh, M.; Boroun, A.R.; Vu, H.; Nguyen, T.; et al. Structurally Designed Attenuated Subunit Vaccines for S. aureus LukS-PV and LukF-PV Confer Protection in a Mouse Bacteremia Model. PLoS ONE 2013, 8, e65384. [Google Scholar] [CrossRef]
- Landrum, M.L.; Lalani, T.; Niknian, M.; Maguire, J.D.; Hospenthal, D.R.; Fattom, A.; Taylor, K.; Fraser, J.; Wilkins, K.; Ellis, M.W.; et al. Safety and Immunogenicity of a Recombinant Staphylococcus aureus α-Toxoid and a Recombinant Panton-Valentine Leukocidin Subunit, in Healthy Adults. Hum. Vaccines Immunother. 2017, 13, 791–801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jones, T. StaphVAX (Nabi). Curr. Opin. Investig. Drugs Lond. Engl. 2000 2002, 3, 48–50. [Google Scholar]
- Staphylococcus aureus Vaccine Conjugate–Nabi: Nabi-StaphVAX, StaphVAX. Drugs RD 2003, 4, 383–385. [CrossRef]
- Asensi, G.F.; de Sales, N.F.F.; Dutra, F.F.; Feijó, D.F.; Bozza, M.T.; Ulrich, R.G.; Miyoshi, A.; de Morais, K.; Azevedo, V.A.d.C.; Silva, J.T.; et al. Oral Immunization with Lactococcus lactis Secreting Attenuated Recombinant Staphylococcal Enterotoxin B Induces a Protective Immune Response in a Murine Model. Microb. Cell Fact. 2013, 12, 32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, W.H.; Pasetti, M.F.; Adhikari, R.P.; Baughman, H.; Douglas, R.; El-Khorazaty, J.; Greenberg, N.; Holtsberg, F.W.; Liao, G.C.; Reymann, M.K.; et al. Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax. Clin. Vaccine Immunol. 2016, 23, 918–925. [Google Scholar] [CrossRef] [Green Version]
- Hu, D.-L.; Omoe, K.; Sasaki, S.; Sashinami, H.; Sakuraba, H.; Yokomizo, Y.; Shinagawa, K.; Nakane, A. Vaccination with Nontoxic Mutant Toxic Shock Syndrome Toxin 1 Protects against Staphylococcus aureus Infection. J. Infect. Dis. 2003, 188, 743–752. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schwameis, M.; Roppenser, B.; Firbas, C.; Gruener, C.S.; Model, N.; Stich, N.; Roetzer, A.; Buchtele, N.; Jilma, B.; Eibl, M.M. Safety, Tolerability, and Immunogenicity of a Recombinant Toxic Shock Syndrome Toxin (RTSST)-1 Variant Vaccine: A Randomised, Double-Blind, Adjuvant-Controlled, Dose Escalation First-in-Man Trial. Lancet Infect. Dis. 2016, 16, 1036–1044. [Google Scholar] [CrossRef]
- Roetzer, A.; Jilma, B.; Eibl, M.M. Vaccine against Toxic Shock Syndrome in a First-in-Man Clinical Trial. Expert Rev. Vaccines 2017, 16, 81–83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brown, L.; Wolf, J.M.; Prados-Rosales, R.; Casadevall, A. Through the Wall: Extracellular Vesicles in Gram-Positive Bacteria, Mycobacteria and Fungi. Nat. Rev. Microbiol. 2015, 13, 620–630. [Google Scholar] [CrossRef] [Green Version]
- Wang, X.; Koffi, P.F.; English, O.F.; Lee, J.C. Staphylococcus aureus Extracellular Vesicles: A Story of Toxicity and the Stress of 2020. Toxins 2021, 13, 75. [Google Scholar] [CrossRef] [PubMed]
- Mattis, D.M.; Spaulding, A.R.; Chuang-Smith, O.N.; Sundberg, E.J.; Schlievert, P.M.; Kranz, D.M. Engineering a Soluble High-Affinity Receptor Domain That Neutralizes Staphylococcal Enterotoxin C in Rabbit Models of Disease. Protein Eng. Des. Sel. PEDS 2013, 26, 133–142. [Google Scholar] [CrossRef] [Green Version]
- Wang, X.; Thompson, C.D.; Weidenmaier, C.; Lee, J.C. Release of Staphylococcus aureus Extracellular Vesicles and Their Application as a Vaccine Platform. Nat. Commun. 2018, 9, 1379. [Google Scholar] [CrossRef] [Green Version]
- da Silveira, S.A.; Perez, A. Improving the Fate of Severely Infected Patients: The Promise of Anti-Toxin Treatments and Superiority Trials. Expert Rev. Anti Infect. Ther. 2017, 15, 973–975. [Google Scholar] [CrossRef] [Green Version]
- Parker, D. Humanized Mouse Models of Staphylococcus aureus Infection. Front. Immunol. 2017, 8, 512. [Google Scholar] [CrossRef]
- Allen, T.M.; Brehm, M.A.; Bridges, S.; Ferguson, S.; Kumar, P.; Mirochnitchenko, O.; Palucka, K.; Pelanda, R.; Sanders-Beer, B.; Shultz, L.D.; et al. Humanized Immune System Mouse Models: Progress, Challenges and Opportunities. Nat. Immunol. 2019, 20, 770–774. [Google Scholar] [CrossRef] [PubMed]
- Mrochen, D.M.; Fernandes de Oliveira, L.M.; Raafat, D.; Holtfreter, S. Staphylococcus aureus Host Tropism and Its Implications for Murine Infection Models. Int. J. Mol. Sci. 2020, 21, 7061. [Google Scholar] [CrossRef] [PubMed]
- Khan, B.A.; Yeh, A.J.; Cheung, G.Y.; Otto, M. Investigational Therapies Targeting Quorum-Sensing for the Treatment of Staphylococcus aureus Infections. Expert Opin. Investig. Drugs 2015, 24, 689–704. [Google Scholar] [CrossRef] [PubMed]
- Kumar, K.; Chen, J.; Drlica, K.; Shopsin, B. Tuning of the Lethal Response to Multiple Stressors with a Single-Site Mutation during Clinical Infection by Staphylococcus aureus. MBio 2017, 8, e01476-17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bojer, M.S.; Lindemose, S.; Vestergaard, M.; Ingmer, H. Quorum Sensing-Regulated Phenol-Soluble Modulins Limit Persister Cell Populations in Staphylococcus aureus. Front. Microbiol. 2018, 9, 255. [Google Scholar] [CrossRef] [PubMed]
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
Ahmad-Mansour, N.; Loubet, P.; Pouget, C.; Dunyach-Remy, C.; Sotto, A.; Lavigne, J.-P.; Molle, V. Staphylococcus aureus Toxins: An Update on Their Pathogenic Properties and Potential Treatments. Toxins 2021, 13, 677. https://doi.org/10.3390/toxins13100677
Ahmad-Mansour N, Loubet P, Pouget C, Dunyach-Remy C, Sotto A, Lavigne J-P, Molle V. Staphylococcus aureus Toxins: An Update on Their Pathogenic Properties and Potential Treatments. Toxins. 2021; 13(10):677. https://doi.org/10.3390/toxins13100677
Chicago/Turabian StyleAhmad-Mansour, Nour, Paul Loubet, Cassandra Pouget, Catherine Dunyach-Remy, Albert Sotto, Jean-Philippe Lavigne, and Virginie Molle. 2021. "Staphylococcus aureus Toxins: An Update on Their Pathogenic Properties and Potential Treatments" Toxins 13, no. 10: 677. https://doi.org/10.3390/toxins13100677