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

Author(s)

Marinho Righetto, Gabriela ; Santos-Filho, Norival Alves ; Catarin Nunes, Leticia Oliveira ; Andre, Camille ; Souza, Julia Medeiros ; Andricopulo, Adriano Defini ; Martins Bispo, Paulo Jose ; Cilli, Eduardo Maffud ; Baratella da Cunha Camargo, Ilana Lopes

• Document type: Journal article
• Source: ACS OMEGA; v. 9, n. 22, p. 13-pg., 2024-05-22.

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. (AU)

• FAPESP's process: 22/05411-8 - Development of peptide/guanidine bioconjugates with anti-Leishmania activity
• Grantee: Eduardo Maffud Cilli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 18/15887-4 - Optimization and elucidation of cationic peptides antibacterial activity in multidrug-resistant pathogens
• Grantee: Gabriela Marinho Righetto
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)