Scorpion venom-derived Opis16a shows potent membrane-destabilising Gram-negative activity and promising in vivo topical efficacy
TL;DR
It is shown that Opis16a rapidly kills Gram-negative bacteria by targeting and disrupting their membranes, with strong bacterial selectivity over HaCaT and HepG2 cell lines.
Abstract
Antimicrobial peptides (AMPs) are lead candidates for antibacterial drug development, especially against multidrug-resistant Gram-negative bacteria. Previously, we showed that Opis16a, a novel scorpion venom-derived AMP, exhibits broad-spectrum activity against drug-resistant Gram-negative strains with minimal toxicity to mammalian cells. However, its mechanism of action remained unclear. Here, we show that Opis16a rapidly kills Gram-negative bacteria by targeting and disrupting their membranes, with strong bacterial selectivity over HaCaT and HepG2 cell lines. Mechanistic studies in Escherichia coli and a clinically relevant multidrug-resistant Acinetobacter baumannii strain reveal that Opis16a interacts with lipopolysaccharides, destabilising the outer membrane and causing inner membrane depolarisation and permeabilisation within minutes. Opis16a’s strong activity (MIC: 8 µg/mL), selectivity, and membrane disruption, along with its serum stability, translates into successful therapy in an in vivo Galleria mellonella model of gentamicin-resistant A. baumannii wound infection. Opis16a emerges as a novel membrane-destabilising AMP with promising potential for topical use against resistant Gram-negative infections.