Converting a Staphylococcus aureus toxin into effective cyclic pseudopeptide antibiotics

Chemistry & Biology
Olivia SoleckiBrice Felden

Abstract

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.

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Citations

Feb 15, 2016·Current Opinion in Microbiology·Régine BrielleBrice Felden
May 11, 2016·Toxins·Christopher F Schuster, Ralph Bertram
Feb 8, 2018·Chemistry : a European Journal·Mathieu LaurencinBaptiste Legrand
May 9, 2019·Toxins·Olga Soutourina
Nov 28, 2019·International Journal of Molecular Sciences·Rawana N AlkhaliliBjörn Canbäck
Sep 10, 2020·Toxins·Marcin RównickiDariusz Bartosik
Aug 7, 2021·Toxins·Sylvie Nonin-LecomteMarie-Laure Pinel-Marie

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