Ultrashort All-Hydrocarbon Stapled α‑Helix Amphiphile as a Potent and Stable Antimicrobial Compound

The ravaging effect of drug-resistant
bacteria has heightened the
need for the development of membrane-soluble antimicrobial peptides
(AMPs). However, their potential for clinical use is hindered by issues
such as poor biocompatibility, salt sensitivity, and proteolytic lability.
In this study, a series of ultrashort stapled cyclization heptapeptides
were obtained by inserting all-hydrocarbon staples. StRRL with the
highest therapeutic index (TI = 36.3) was selected after evaluating
its antibacterial and toxic activity. Furthermore, stRRL demonstrated
exceptional performance in high-protease and high-salt environments,
making it an effective weapon against bacteria like Escherichia coli in a mouse peritonitis-sepsis model.
The membrane lytic mechanism of stRRL, which operates from outside
to inside, gives it a low drug-resistant tendency. This suggests that
stRRL has the potential to replace antibiotics as a powerful candidate
in tackling bacterial infection. In conclusion, the ultrashort all-hydrocarbon
stapled antimicrobial amphiphiles inaugurated a novel entrance to
the advancements of highly stable peptide compounds.