Sequence-activity relationship, and mechanism of action of mastoparan analogues against extended-drug resistant Acinetobacter baumannii

Abstract

The treatment of some infectious diseases can currently be very challenging since the spread of multi-, extended- or pan-resistant bacteria has considerably increased over time. On the other hand, the number of new antibiotics approved by the FDA has decreased drastically over the last 30 years. The main objective of this study was to investigate the activity of wasp peptides, specifically mastoparan and some of its derivatives against extended-resistant Acinetobacter baumannii. We optimized the stability of mastoparan in human serum since the specie obtained after the action of the enzymes present in human serum is not active. Thus, 10 derivatives of mastoparan were synthetized. Mastoparan analogues (guanidilated at the N-terminal, enantiomeric version and mastoparan with an extra positive charge at the C-terminal) showed the same activity against Acinetobacter baumannii as the original peptide (2.7 μM) and maintained their stability to more than 24 h in the presence of human serum compared to the original compound. The mechanism of action of all the peptides was carried out using a leakage assay. It was shown that mastoparan and the abovementioned analogues were those that released more carboxyfluorescein. In addition, the effect of mastoparan and its enantiomer against A. baumannii was studied using transmission electron microscopy (TEM). These results suggested that several analogues of mastoparan could be good candidates in the battle against highly resistant A. baumannii infections since they showed good activity and high stability.

Bee venom-derived antimicrobial peptide melectin has broad-spectrum potency, cell selectivity, and salt-resistant properties

“…The components of bee venom have been extensively studied for their biological, toxicological, and pharmacological actions. The venom peptides mastoparan and melittin exhibit antimicrobial activity towards a broad range of bacteria 21,22 . Melittin is a representative bee venom peptide with 26 amino acids and is known to have excellent antimicrobial activity but high cytotoxicity in mammalian cells 23 .…”

Antimicrobial and Antibiofilm Effects of Peptides from Venom of Social Wasp and Scorpion on Multidrug-Resistant Acinetobacter baumannii

“…AMPs derived from wasp and scorpion venom have been widely tested against different microorganisms and have a microbicidal function on bacteria and fungi, besides having antiviral action [33]. Although the bactericidal activity of Agelaia-MPI against Gram-negative bacteria was not tested before, we believe that it could involve the interaction of the peptide with negatively-charged molecules on the surface of bacteria that would cause disruption of bacterial membranes [31,55]. Because AMPs acts on the lipid portion of cellular membranes, it is believed that they could avoid the development of resistance mechanisms such as those commonly induced by antibiotics, i.e., A. baumannii bacterial resistance mechanisms to conventional antibiotics comprises multidrug efflux pumps, aminoglycoside-modifying enzymes, selective membrane permeability, alteration of target sites, and hydrolytic enzymes like carbapenemase [56,57,58].…”

Activity of synthetic peptides against Chlamydia

“…In several organisms, antimicrobial peptides, as components of the innate immune system, represent the first barrier against microbial infections and can interact with different targets such as membranes, cell wall, nucleic acid or cytosolic proteins . The mechanism of action of antimicrobial peptides is primarily related to the global positive charge of most of them, leading to interaction with anionic microorganism membranes, leading to the formation of pores, or acting as detergents, among other membrane level mechanisms of action …”

“…With regard to the antimicrobial peptides used in this study, it is known that CMO interacts with bacterial lipid bilayers resulting in drastic changes in membrane morphology, Mastoparan analogues (with an extra positive charge at the C‐terminal) cause disruption of bacterial membrane and Pa ‐MAP antimicrobial activity can be attributed mostly to its hydrophobic interactions . CMO has demonstrated antimicrobial activity against S. aureus and K. pneumoniae , with mastoparan analogues working against Acinetobacter baumannii and Pa ‐MAP against S. aureus and E. coli…”

“…Due to these facts, the formulation of synthetic peptides with improved solubility and antimicrobial activity and lower toxic effects towards mammalian cells has become extremely attractive . The good activity of synthetic peptides, such as the wasp‐generated peptide mastoparan, clavanins (cationic α‐helical peptides from the marine tunicate Styela clava ), and Pa ‐MAP (an alanine‐rich peptide with hydrophobic amino acid residues from the polar fish Pleuronectes americanus ) against some Gram‐positive and Gram‐negative bacteria has been reported …”