Enhancing antimicrobial activity through structural modification of Rip-thanatin with amino acid substitution

Rip-thanatin (RipT), a natural antimicrobial peptide derived from Riptortus pedestrisc, is comprised of 18 amino acid residues. Herein, a series of Rip-thanatin derivatives were synthesized using cationic and amphiphilic design strategies of antimicrobial peptides (AMPs) by employing an amino acid replacement method. The results revealed that the cationic amino acid, arginine, exhibited superior antibacterial activity compared to lysine residues. Substituting lysine with arginine in Rip-thanatin enhanced the penetration of the derivatives into the cell membrane. The findings indicated that amphiphilicity, rather than hydrophobicity, serves as the primary physiochemical parameter influencing the bacterial killing efficacy of the β-sheet peptide derivatives. Together, our research establishes a framework for optimizing Rip-thanatin derivatives, that provided valuable insights for the development of antimicrobial drugs.