TAG‐Assisted Liquid‐Phase Synthesis and Structure Activity Relationship of Macolacin‐Based Side‐to‐Tail Cyclopeptides Antibiotic

Comprehensive Summary TAG‐assisted peptide synthesis technology enables optimal conservation of Fmoc amino acid raw materials and chemical solvents while eliminating the need for intricate chromatographic purification processes. This work presents a 4,4'‐diphenylphosphonoxy diphenylcarbinol tag‐mediated liquid‐phase synthesis approach for preparing side‐to‐tail cyclopeptides macolacin which has strong activity against gram‐negative bacteria, and its 15 analogues containing four N‐methylation modified cyclopeptides, as well as an investigation of their structure‐activity relationship (SAR). The synthesis of macolacin analogues primarily focuses on the modifications of the N‐methylation group of Ile‐7 and the tail fatty acyl chain of macolacin. The incorporation of N‐methylation for Ile‐7, along with the dihalogenated or monohalogenated benzoic acids for tail modification, exhibited remarkable antibacterial efficacy and minimal hepatocellular toxicity in vitro. The present study identified an N‐methylation‐modified antimicrobial cyclopeptide Ma14 that exhibits rapid bactericidal efficacy against A. baumanii, etc., while showing reduced hepatocellular toxicity. Molecular docking simulations were conducted to investigate the binding of cyclopeptides to the outer membrane protein BamA of A. baumannii. The findings demonstrated the stable binding interactions of the cyclopeptides with the BamA protein and then presented a novel approach to explain the bacteriostatic mechanism of macolacin‐based cyclopeptide antibiotics. The study presented tag‐assisted liquid phase total synthesis and the structure‐activity relationship of macolacin‐based antibiotic, and identified Ma14 as bactericidal agent against A. baumannii.