Biphenyl-macolacin derivatives with enhanced antibacterial activity against Gram-negative pathogens discovered via LTIS strategy.

The global rise in antimicrobial resistance (AMR), particularly in Gram-negative bacteria like Escherichia coli, presents a critical public health challenge. Current antibiotics often lack efficacy against these resistant pathogens, including colistin-resistant strains, necessitating novel therapeutic approaches. Biphenyl-macolacin (Bip-macolacin) is a promising candidate, but efficient structural optimization is crucial to overcome resistance mechanisms and develop new antibiotics. This study addresses the need for systematic strategies to enhance its potency and spectrum against these difficult-to-treat infections.

Researchers employed a novel Lysine-T/CDHA iterative scanning (LTIS) strategy to systematically modify the antibiotic Biphenyl-macolacin. This approach aimed to identify modifiable sites on the Bip-macolacin structure, crucial for targeted optimization. Following the LTIS, structural derivatization was performed using chemical ligation chemistry, allowing for the convenient preparation of four distinct classes of Bip-macolacin derivatives. The efficacy of representative analogues, specifically 5, 18, and 46, was further evaluated through resistance development evaluation and hemolysis assays to assess their antibacterial potential and safety profile against various bacterial strains.