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1.
Sci Rep ; 6: 35465, 2016 11 02.
Article in English | MEDLINE | ID: mdl-27804992

ABSTRACT

Antibiotic-resistant infections are predicted to kill 10 million people per year by 2050, costing the global economy $100 trillion. Therefore, there is an urgent need to develop alternative technologies. We have engineered a synthetic peptide called clavanin-MO, derived from a marine tunicate antimicrobial peptide, which exhibits potent antimicrobial and immunomodulatory properties both in vitro and in vivo. The peptide effectively killed a panel of representative bacterial strains, including multidrug-resistant hospital isolates. Antimicrobial activity of the peptide was demonstrated in animal models, reducing bacterial counts by six orders of magnitude, and contributing to infection clearance. In addition, clavanin-MO was capable of modulating innate immunity by stimulating leukocyte recruitment to the site of infection, and production of immune mediators GM-CSF, IFN-γ and MCP-1, while suppressing an excessive and potentially harmful inflammatory response by increasing synthesis of anti-inflammatory cytokines such as IL-10 and repressing the levels of pro-inflammatory cytokines IL-12 and TNF-α. Finally, treatment with the peptide protected mice against otherwise lethal infections caused by both Gram-negative and -positive drug-resistant strains. The peptide presented here directly kills bacteria and further helps resolve infections through its immune modulatory properties. Peptide anti-infective therapeutics with combined antimicrobial and immunomodulatory properties represent a new approach to treat antibiotic-resistant infections.


Subject(s)
Anti-Bacterial Agents/pharmacology , Immunologic Factors/pharmacology , Peptides/pharmacology , Animals , Bacterial Infections/drug therapy , Blood Proteins/pharmacology , Disease Models, Animal , Female , HEK293 Cells , Humans , Immunity, Innate/drug effects , Immunomodulation/drug effects , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Peptides/chemistry , Peptides/therapeutic use , Peptides/toxicity , RAW 264.7 Cells
2.
Antimicrob Agents Chemother ; 59(4): 2113-21, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25624332

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.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Anura/metabolism , Peptides/therapeutic use , Skin Diseases, Bacterial/drug therapy , Staphylococcal Infections/drug therapy , Trypsin Inhibitors/therapeutic use , Animals , Anti-Bacterial Agents/chemical synthesis , Cell Survival/drug effects , Cyclization , Female , Humans , In Vitro Techniques , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Models, Molecular , Peptides/chemical synthesis , Peptides/chemistry , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Skin Diseases, Bacterial/microbiology , Staphylococcal Infections/microbiology , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry
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