Optimizing Bothropstoxin-I-Derived Peptides: Exploring the Antibacterial Potential of p-BthW

TL;DR

Scientists optimized a peptide from Bothropstoxin-I to create a potent, low-hemolytic antibacterial agent with resistance-reducing properties.

Contribution

A novel peptide analogue, p-BthW, was synthesized with improved antibacterial activity and resistance profile.

Findings

p-BthW showed potent antibacterial activity at lower concentrations with low hemolysis.

p-BthW exhibited a quick bactericidal effect and prolonged post-antibiotic effect similar to polymyxin B.

The peptide's mechanism involves membrane depolarization and necrosis-like effects in Gram-negative bacteria.

Abstract

Antimicrobial peptides
are an emerging class of antibiotics that
present a series of advantageous characteristics such as wide structural
variety, broad spectrum of activity, and low propensity to select
for resistance. They are found in all classes of life as defense molecules.
A group of peptides derived from the protein Bothropstoxin-I has been
previously studied as an alternative treatment against multi-drug-resistant
bacteria. The peptide p-BthTX-I (sequence: KKYRYHLKPFCKK) and its
homodimer, linked by disulfide oxidation through the residues of Cys11
and the serum degradation product [sequence: (KKYRYHLKPFC)2], were evaluated and showed similar antimicrobial activity. In this
study, we synthesized an analogue of p-BthTX-I that uses the strategy
of Fmoc-Lys(Fmoc)-OH in the C-terminal region for dimerization and
tryptophan for all aromatic amino acids to provide better membrane
interactions. This analogue, named p-BthW, displayed potent antibacterial
activity at lower concentrations and maintained the same hemolytic
levels as the original molecule. Our assessment revealed that p-BthW
has a quick in vitro bactericidal action and prolonged post-antibiotic
effect, comparable to the action of polymyxin B. The mode of action
of p-BthW seems to rely not only on membrane depolarization but also
on necrosis-like effects, especially in Gram-negative bacteria. Overall,
the remarkable results regarding the propensity to develop resistance
reaffirmed the great potential of the developed molecule.

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