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

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.

Prediction and Characterization of Cationic Arginine-Rich Plant Antimicrobial Peptide SM-985 From Teosinte (Zea mays ssp. mexicana)

“…The 3D structural model of SM-985 was predicted using the I-TASSER server, and this model was validated with ProSA-web and MolProbity software. The ProSA-web results showed that the SM-985 3D model was within the favorable region of structures, and these results were comparable to a previous study (Liscano et al, 2019). The results of MolProbity indicated that the peptide structure parameters remained within the limits of acceptable quality and stability (Beg et al, 2018).…”

A Novel Cecropin D-Derived Short Cationic Antimicrobial Peptide Exhibits Antibacterial Activity Against Wild-Type and Multidrug-Resistant Strains of Klebsiella pneumoniae and Pseudomonas aeruginosa

“…This flexibility in the central region of the peptide reflects a hinge that facilitates contact with the nonpolar region of phospholipids, allowing the peptide to be inserted into the K pneumoniae membrane. 66 In contrast, the peptide remained stable most of the time in the P aeruginosa membrane, except for a slight variation in the amino-terminal end at 3 ns ( Figure 5). Stability is also an important structural property for antibacterial activity.…”

Development of Polyelectrolyte Complex Nanoparticles-PECNs Loaded with Ampicillin by Means of Polyelectrolyte Complexation and Ultra-High Pressure Homogenization (UHPH)

“…[85]. In contrast, the PAM-18Na-EuCl family, where the complex surface consists mainly of the EuCl polymer (Figure 4), these could interact electrostatically with the bacterial surface, which is rich in anionic phospholipids such as phosphatidylglycerol [86], achieving a membrane-destabilizing effect and allowing the passage of water-soluble molecules [83]. On the other hand, the sizes exhibited by the PECNs (Figure 2) prevents them from entering through the pores of the bacteria cell wall since the latter have sizes between 2.03 and 3 nm [87].…”