Discovery of synthetic penaeidin activity against antibiotic-resistant fungi.
Penaeidins are antimicrobial peptides from shrimp that are constituted by divergent classes of peptide isoforms in an individual organism. Penaeidin sequence variation suggests functional diversity in the host and promises differential activities if applied to treat infections in humans. We have synthesized isoform 4 of penaeidin class 3 from the Atlantic shrimp, Litopenaeus setiferus, by native ligation using three peptide segments. Our synthesis approach led to the discovery of an irreversible side reaction that was successfully suppressed, a discovery, which has particular relevance to the synthesis of cysteine-rich peptides. The antimicrobial activity of full-length penaeidin and the N-terminal proline-rich domain of this isoform were compared with the corresponding peptides of penaeidin class 4 isoform 1 using a wide range of bacteria and fungi. New aspects of penaeidin function are reported that include activity against fungi of the phylum Basidiomycota (Cryptococcus strains), activity against fungi that are pathogenic to humans and effectiveness in the context of antibiotic resistance mechanisms (Cryptococcus and Candida spp.). The proline-rich domain of penaeidin class 4 shows the highest relative antimicrobial activity, while exhibiting no cytotoxicity to human monocytes, and therefore stands out as a potential peptide therapeutic.
Cuthbertson
Brandon J
BJ
National Institutes of Health/National Institute of Environmental Health Sciences, PO Box 12233 MD F3-04, Research Triangle Park, NC 27709-2233, USA. cuthbertsonb@niehs.nih.gov
Büllesbach
Erika E
EE
Gross
Paul S
PS
D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004352:Drug Resistance, Microbial; D005658:Fungi / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D023181:Antimicrobial Cationic Peptides; C501426:penaeidin-4 protein, Litopenaeus setiferus