Increases in Hydrophilicity and Charge on the Polar Face of Alyteserin 1c Helix Change its Selectivity towards Gram-Positive Bacteria.

Yamil Liscano,Lina Vargas,Valentina Laverde-Rojas,José Oñate-Garzón,Stefania Cantor,Constain H Salamanca

doi:10.3390/antibiotics8040238

Yamil Liscano, Lina Vargas + Show 4 more

Open Access

https://doi.org/10.3390/antibiotics8040238

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Journal: Antibiotics	Publication Date: Nov 27, 2019
Citations: 35	License type: CC BY 4.0

Affiliation: University of Antioquia, Universidad Santiago de Cali

Abstract

Recently, resistance of pathogens towards conventional antibiotics has increased, representing a threat to public health globally. As part of the fight against this, studies on alternative antibiotics such as antimicrobial peptides have been performed, and it has been shown that their sequence and structure are closely related to their antimicrobial activity. Against this background, we here evaluated the antibacterial activity of two peptides developed by solid-phase synthesis, Alyteserin 1c (WT) and its mutant derivative (ΔM), which shows increased net charge and reduced hydrophobicity. These structural characteristics were modified as a result of amino acid substitutions on the polar face of the WT helix. The minimum inhibitory concentration (MIC) of both peptides was obtained in Gram-positive and Gram-negative bacteria. The results showed that the rational substitutions of the amino acids increased the activity in Gram-positive bacteria, especially against Staphylococcus aureus, for which the MIC was one-third of that for the WT analog. In contrast to the case for Gram-positive bacteria, these substitutions decreased activity against Gram-negative bacteria, especially in Escherichia coli, for which the MIC was eight-fold higher than that exhibited by the WT peptide. To understand this, models of the peptide behavior upon interacting with membranes of E. coli and S. aureus created using molecular dynamics were studied and it was determined that the helical stability of the peptide is indispensable for antimicrobial activity. The hydrogen bonds between the His20 of the peptides and the phospholipids of the membranes should modulate the selectivity associated with structural stability at the carboxy-terminal region of the peptides.

Highlights

Antimicrobial peptides (AMPs) are molecules produced via innate immunity, which are expressed by the host when challenged by an infectious agent [1]
Net charge is an essential property for antimicrobial activity, since it is responsible for the initial interaction between the peptide and the anionic membranes of the pathogens, while hydrophobic residues contribute to the insertion of the peptide into the hydrophobic membrane core [7,8]
The WT peptide composed of 23 amino acid residues has on its polar face an anionic residue (E4), two hydrophobic residues (A8 and A18), and a neutral polar residue (S12)

Summary

Introduction

Antimicrobial peptides (AMPs) are molecules produced via innate immunity, which are expressed by the host when challenged by an infectious agent [1] These molecules generally exert their antimicrobial activity via interaction with the anionic membranes of the microorganisms, altering the phospholipid packaging while integrity and permeability are lost [2], killing the microorganism. For this reason, the development of resistance to AMPs is lower than that to conventional antibiotics [3], which are typically directed towards specific targets, especially proteins [4]. The α-helix is one of the most common structures in peptides, with hydrophobic residues on one side of the helix and cationic/hydrophilic residues on the other, and both sides of the helix being important for antibacterial activity [7]

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Discussion

Conclusion