Converting a Staphylococcus aureus toxin into effective cyclic pseudopeptide antibiotics.
Staphylococcus aureus produces peptide toxins that it uses to respond to environmental cues. We previously characterized PepA1, a peptide toxin from S. aureus, that induces lytic cell death of both bacterial and host cells. That led us to suggest that PepA1 has an antibacterial activity. Here, we demonstrate that exogenously provided PepA1 has activity against both Gram-positive and Gram-negative bacteria. We also see that PepA1 is significantly hemolytic, thus limiting its use as an antibacterial agent. To overcome these limitations, we converted PepA1 into nonhemolytic derivatives. Our most promising derivative is a cyclic heptapseudopeptide with inconsequential toxicity to human cells, enhanced stability in human sera, and sharp antibacterial activity. Mechanistically, linear and helical PepA1 derivatives form pores at the bacterial and erythrocyte surfaces, while the cyclic peptide induces bacterial envelope reorganization, with insignificant action on the erythrocytes. Our work demonstrates that bacterial toxins might be an attractive starting point for antibacterial drug development.
U835 Inserm, Pharmaceutical Biochemistry, 2 Avenue du Professeur Léon Bernard, Rennes University, 35043 Rennes, France.
Olivia
O
Solecki
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Rennes University, Beaulieu, 35042 Rennes, France.
Amor
A
Mosbah
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Rennes University, Beaulieu, 35042 Rennes, France. Electronic address: michele.baudy-floch@univ-rennes1.fr.
Michèle
M
Baudy Floc'h
U835 Inserm, Pharmaceutical Biochemistry, 2 Avenue du Professeur Léon Bernard, Rennes University, 35043 Rennes, France. Electronic address: brice.felden@univ-rennes1.fr.
Brice
B
Felden
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics*; D001427:Bacterial Toxins / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D053878:Hemolytic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology; D015202:Protein Engineering; D013211:Staphylococcus aureus / Q000737:chemistry / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D053878:Hemolytic Agents; D010456:Peptides, Cyclic