Polyalanine peptide variations may have different mechanisms of action against multidrug-resistant bacterial pathogens

Abstract

Objectives The number of bacterial pathogens resistant to the currently available antibiotics has dramatically increased, with antimicrobial peptides (AMPs) being among the most promising potential new drugs. In this study, the applicability and mechanisms of action of Pa-MAP 2 and Pa-MAP 1.9, two AMPs synthetically designed based on a natural AMP template, were evaluated. Methods Pa-MAP 2 and Pa-MAP 1.9 were tested against a clinically isolated multidrug-resistant (MDR) Escherichia coli strain. Biophysical approaches were used to evaluate the preference of both peptides for specific lipid membranes, and bacterial surface changes imaged by atomic force microscopy (AFM). The efficacy of both peptides was assessed both in vitro and in vivo. Results Experimental results showed that both peptides have antimicrobial activity against the E. coli MDR strain. Zeta potential and surface plasmon resonance assays showed that they interact extensively with negatively charged membranes, changing from a random coil structure, when free in solution, to an α-helical structure after membrane interaction. The antibacterial efficacy was evaluated in vitro, by several techniques, and in vivo, using a wound infection model, showing a concentration-dependent antibacterial effect. Different membrane properties were evaluated to understand the mechanism underlying peptide action, showing that both promote destabilization of the bacterial surface, as imaged by AFM, and change properties such as membrane surface and dipole potential. Conclusions Despite their similarity, data indicate that the mechanisms of action of the peptides are different, with Pa-MAP 1.9 being more effective than Pa-MAP 2. These results highlight their potential use as antimicrobial agents against MDR bacteria.

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“…In recent years, AMPs have been widely investigated as a promising alternative to conventional drugs in the treatment of infections caused by pathogenic microorganisms (Biswaro et al, 2018; Cardoso et al, 2016; Felício et al, 2021; Gomes et al, 2018; Makowski et al, 2019; Makowski et al, 2020). Some AMPs exhibit broad‐spectrum activity against bacteria, fungi, viruses, and/or protozoa (Aguiar et al, 2020; Felício et al, 2021; Gomes et al, 2018; Makowski et al, 2020). These antimicrobials may also present other activities such as an immunomodulation, anti‐tumor or even regenerative action (Biswaro et al, 2018; Gomes et al, 2018; Makowski et al, 2019).…”

Antimicrobial peptides against polymyxin-resistant Klebsiella pneumoniae: a patent review

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