Host Defense Peptide Piscidin and Yeast-derived Glycolipid Exhibit Synergistic Antimicrobial Action through Concerted Interactions with Membranes

Published

October 19, 2023

Author(s)

Fei Liu, Alexander Greenwood, Yawei Xiong, Rebecca Miceli, Riqiang Fu, Kyle Anderson, Scott McCallum, Ella Mihailescu, Richard Gross, Myriam Cotten

Abstract

Developing new antimicrobials as alternatives to conventional antibiotics has become an urgent race to eradicate drug-resistant bacteria and save human lives. Conventionally, antimicrobial molecules are studied independently even though they can be co-secreted in vivo. In this research, we investigate two classes of naturally-derived antimicrobials: sophorolipid (SL) esters as modified yeast-derived glycolipid biosurfactants that feature high biocompatibility and low production cost; and piscidins, which are host defense peptides (HDPs) from fish. While HDPs such as piscidins target the membrane of pathogens, and thus result in low incidence of resistance, SLs are not well understood on a mechanistic level. Here, we demonstrate that combining SL-hexyl ester (SL-HE) with sub-inhibitory concentration of piscidins 1 (P1) and 3 (P3) boosts its antimicrobial action by at least two orders of magnitude, potentiating a promising therapeutic window. Permeabilization assays and biophysical studies employing circular dichroism, NMR, mass spectrometry, and X-ray diffraction are performed to investigate the mechanism underlying this powerful synergy. We reveal four key mechanistic features underlying the synergistic action: 1) P1/3 binds to SL-HE aggregates, becoming α-helical; 2) piscidin-glycolipid assemblies synergistically accumulate on membranes; 3) SL-HE used alone or bound to P1/3 associates with phospholipid bilayers where it induces defects; 4) piscidin-glycolipid complexes disrupt the bilayer structure more dramatically and differently than either compound alone, with phase separation occurring when both agents are present. Overall, dramatic enhancement in antimicrobial activity is associated with the use of two membrane-active agents, with the glycolipid playing the roles of pre-folding the peptide, coordinating the delivery of both agents to bacterial surfaces, recruiting the peptide to the pathogenic membranes, and supporting membrane disruption by the peptide. Given that SLs are ubiquitously and safely used in consumer products, the SL/peptide formulation engineered and mechanistically characterized in this study could represent fertile ground to develop novel synergistic agents against drug-resistant bacteria.

Citation

JACS Au

Pub Type

Journals

Download Paper

https://doi.org/10.1021/jacsau.3c00506

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Citation

Liu, F. , Greenwood, A. , Xiong, Y. , Miceli, R. , Fu, R. , Anderson, K. , McCallum, S. , Mihailescu, E. , Gross, R. and Cotten, M. (2023), Host Defense Peptide Piscidin and Yeast-derived Glycolipid Exhibit Synergistic Antimicrobial Action through Concerted Interactions with Membranes, JACS Au, [online], https://doi.org/10.1021/jacsau.3c00506, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=956568 (Accessed April 28, 2024)