title: In vivo efficacy of anuran trypsin inhibitory peptides against staphylococcal skin infection and the impact of peptide cyclization.
abstract: Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg(-1). Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: U
authors.initials: U
authors.lastname: Malik
authors.affiliation: Centro de Análises Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brasília, Brazil.
authors.forename: O N
authors.initials: ON
authors.lastname: Silva
authors.affiliation: Centro de Análises Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brasília, Brazil.
authors.forename: I C M
authors.initials: IC
authors.lastname: Fensterseifer
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: L Y
authors.initials: LY
authors.lastname: Chan
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
authors.forename: R J
authors.initials: RJ
authors.lastname: Clark
authors.affiliation: Centro de Análises Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brasília, Brazil S-Inova, Universidade Catolica Dom Bosco, Campo Grande, MS, Brazil.
authors.forename: O L
authors.initials: OL
authors.lastname: Franco
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia Australian Institute of Tropical Health and Medicine, Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Cairns, Australia.
authors.forename: N L
authors.initials: NL
authors.lastname: Daly
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia d.craik@imb.uq.edu.au.
authors.forename: D J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D001001:Anura / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D017192:Skin Diseases, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D010456:Peptides, Cyclic; C448501:SFTI-1 peptide, sunflower; D014361:Trypsin Inhibitors