Effect of Non-natural Hydrophobic Amino Acids on the Efficacy and Properties of the Antimicrobial Peptide C18G
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Effect of Non-natural Hydrophobic Amino Acids on the Efficacy and Properties of the Antimicrobial Peptide C18G Morgan A. Hitchner 1 & Matthew R. Necelis 1 & Devanie Shirley 1 & Gregory A. Caputo 1,2
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Antimicrobial peptides (AMPs) have been an area of great interest, due to the high selectivity of these molecules toward bacterial targets over host cells and the limited development of bacterial resistance to these molecules through evolution. The peptides are known to selectively bind to bacterial cell surfaces through electrostatic interactions, and subsequently, the peptides insert into the cell membrane and cause local disruptions of membrane integrity leading to cell death. Previous experiments showed that replacing the Leu residues in the AMP C18G with other naturally occurring hydrophobic residues resulted in side-chaindependent activities. This work extends the investigation to non-natural hydrophobic amino acids and the effect on peptide activity. Minimal inhibitory concentration (MIC) results demonstrated that amino acid substitutions containing long flexible carbon chains maintained or increased antimicrobial activity compared to natural analogues. In solution, the peptide showed aggregation only with the most hydrophobic non-natural amino acid substitutions. Binding assays using Trp fluorescence confirm a binding preference for anionic lipids while quenching experiments demonstrated that the more hydrophobic peptides are more deeply buried in the anionic lipid bilayers compared to the zwitterionic bilayers. The most effective peptides at killing bacteria were also those which showed some level of disruption of bacterial membranes; however, one peptide sequence exhibited very strong activity and very low levels of red blood cell hemolysis, yielding a promising target for future development. Keywords Antimicrobial peptides . Fluorescence . Lipid binding . C18G . Membrane permeabilization
Introduction Although the first case of antibiotic resistance was identified in 1940, resistance development has rapidly increased since the late 1990s [1]. Despite this, there has been a significant decrease in the number of new antibiotics developed and through clinical trials during this same period. The development of new antibiotics is primarily hampered due to the economic challenges of developing these compounds that will rapidly lose viability in the clinic due to resistance development [1, 2]. The World Health Organization and the US Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12602-020-09701-3) contains supplementary material, which is available to authorized users. * Gregory A. Caputo [email protected] 1
Department of Chemistry and Biochemistry, Rowan University, 201 Mullica Hill Road, Glassboro, NJ 08028, USA
2
Department of Molecular and Cellular Biosciences, Rowan University, 201 Mullica Hill Road, Glassboro, NJ 08028, USA
Centers for Disease Control have both identified antimicr
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