Speakers
Description
Antibiotic resistance continues to compromise the effectiveness of existing therapies and heightens the risk of serious public health outcomes, posing a significant global health threat. Naturally occurring antimicrobial peptides (AMPs), essential components of innate immunity, offer a promising alternative to conventional antibiotics due to their broad-spectrum activity and lower propensity for resistance development. However, their clinical utility is often limited by cytotoxicity, particularly hemolysis of non-target mammalian cells. This study aimed to engineer and optimize an AMP derived from the venom of the Trinidad Thick-tailed scorpion (Tityus trinitatis) to enhance antimicrobial potency while reducing hemolytic activity. We focused on TtAP-3, a 17-amino-acid peptide with established antimicrobial properties and moderate hemolytic effects. Using an In-silico approach, molecular dynamics (MD) simulations were employed to investigate the peptide’s interactions with bacterial and mammalian membranes, assessing binding, membrane penetration, conformational dynamics, and stability. Key residues governing activity and selectivity were identified, and rational single and double amino acid substitutions were introduced to improve bacterial membrane affinity while reducing interactions with mammalian cells. Top-performing variants were subjected to additional MD simulations, which confirmed improved structural behavior, enhanced antimicrobial interactions, and reduced hemolytic potential. These results highlight the utility of computational methods in AMP optimization and provide a promising framework for the development of safer, more effective antimicrobial agents. The optimized peptides warrant further experimental validation and may contribute to the next generation of peptide-based therapeutics to address antibiotic resistance.