Antibiotic resistance is one of the greatest threats facing mankind in 21<sup>st</sup> century. Host-defense peptides (HDPs) have the potential to combat emerging drug-resistant bacteria through disruption of their membranes, such as the helical magainin 2 and its analogs. They adopt cationic amphipathic conformations upon interaction with bacterial membranes, leading to membrane disruption and bacterial cell death. We have previously reported that amphipathic sulfono-γ-AApeptides exhibit bactericidal activity by mimicking magainin 2. Here we demonstrate for the first time that amphipathic helical 1:1 α/sulfono-γ-AA heterogeneous peptides, in which regular amino acids and sulfono-γ-AApeptide building blocks are alternatively present in a 1:1 pattern, display potent antibacterial activity against both Gram-positive and Gram-negative bacterial pathogens. Small Angle X-ray Scattering (SAXS), fluorescence microscopy and time-kill experiments indicate that the lead sequences adopt defined helical structures and exert antimicrobial activity by mimicking the mechanism of HDPs. Our results certify the effective design of a new class of helical foldamer, which may lead to the development of HDP-mimicking antimicrobial peptidomimetics that combat drug-resistant bacterial pathogens in the future.

Helical 1:1 α/sulfono-γ-AA heterogeneous peptides with antibacterial activity

254th National Meeting (2017)

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