STUDY THE EFFECT OF CONJUGATED NOVEL ULTRASHORT ANTIMICROBIAL PEPTIDES IN COMBINATION WITH FARNESYL AGAINST RESISTANCE STRAINS OF PSEUDOMONAS AERUGINOSA

Objective: The objective of this study was to design and evaluate a novel ultrashort antimicrobial peptide, San-112003, structurally conjugated with a farnesyl chain, for its potential antibacterial activity against both antibiotic-susceptible and multi-drug-resistant (MDR) strains of Pseudomonas aeruginosa. Given the rising threat of antimicrobial resistance and the limitations of conventional antibiotics, antimicrobial peptides (AMPs) are explored as a promising alternative. This study aimed to assess the efficacy, toxicity, and potential synergism of San-112003 with conventional antibiotics. Methods: In this study, we designed and synthesized a novel ultrashort antimicrobial peptide, San-112003, which incorporates repeating tripeptide units (tryptophan–arginine–glycine) chemically conjugated to a farnesyl chain. This structural design enhances membrane targeting and antimicrobial potency. The antimicrobial efficacy of San-112003 was evaluated against both antibiotic-susceptible and MDR strains of P. aeruginosa. Hemolytic toxicity assays were conducted on human red blood cells, and synergy studies were performed in combination with conventional antibiotics, including gentamicin. Results: San-112003 was successfully synthesized with 99% purity and correct molecular mass confirmation. The peptide showed low cytotoxicity in MTT assays across tested concentrations. It demonstrated potent bactericidal activity against Pseudomonas aeruginosa, with MIC and MBC values of 0.5 µg/ml for the control strain and 2.5 µg/ml for the MDR strain. Hemolysis testing indicated minimal toxicity at concentrations relevant to antimicrobial activity. Synergy testing revealed the greatest enhancement in bacterial inhibition when combined with gentamicin, with FICI values of 0.075 for the control strain and 0.20 for the MDR strain. Additionally, the peptide–antibiotic combinations reduced bacterial biofilm viability more effectively than the peptide alone. Conclusion: San-112003 is a promising AMP–farnesyl conjugate with potent activity against P. aeruginosa, including MDR strains. Its synergism with gentamicin and low hemolytic toxicity suggest that AMP–antibiotic combinations could serve as a valuable strategy against antibiotic resistance.