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<p>The antibiotic biphenyl-macolacin (Bip-macolacin) is a promising drug candidate with good activity against Gram-negative bacteria including several colistin-resistant pathogens, providing a potential structural motif for developing novel antibiotics. Considering the importance of efficient and effective structural optimization in medicinal chemistry studies, we herein report a lysine-T/CDHA iterative scanning (LTIS) strategy to produce Bip-macolacin analogues and identify the modifiable sites, followed by structural derivatization through chemical ligation chemistry. Using this approach, four classes of Bip-macolacin derivatives were prepared conveniently, several of which exhibited antibacterial activities comparable or better than those of Bip-macolacin. The efficacy of representative analogues <b>5</b>, <b>18</b>, and <b>46</b> was also demonstrated by the resistance development evaluation and hemolysis assay. From this study, a systematic structure-activity relationship of Bip-macolacin was established as a reference for further development of Bip-macolacin-based antibiotics. This novel and powerful strategy also provides more opportunities and valuable options for the structural optimization in future research on peptide therapeutics.</p> Graphical abstract <p></p>

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Discovery of potent biphenyl-macolacin derivatives through a lysine-T/CDHA iterative scanning (LTIS) strategy followed by chemical ligation-based modifications

  • 期刊论文

  • 发表日期：

    2026年7月11日

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  • Xiaoshu Jing,
  • Kaixuan Song,
  • Biyao Liu,
  • Kang Jin

摘要

The antibiotic biphenyl-macolacin (Bip-macolacin) is a promising drug candidate with good activity against Gram-negative bacteria including several colistin-resistant pathogens, providing a potential structural motif for developing novel antibiotics. Considering the importance of efficient and effective structural optimization in medicinal chemistry studies, we herein report a lysine-T/CDHA iterative scanning (LTIS) strategy to produce Bip-macolacin analogues and identify the modifiable sites, followed by structural derivatization through chemical ligation chemistry. Using this approach, four classes of Bip-macolacin derivatives were prepared conveniently, several of which exhibited antibacterial activities comparable or better than those of Bip-macolacin. The efficacy of representative analogues 5, 18, and 46 was also demonstrated by the resistance development evaluation and hemolysis assay. From this study, a systematic structure-activity relationship of Bip-macolacin was established as a reference for further development of Bip-macolacin-based antibiotics. This novel and powerful strategy also provides more opportunities and valuable options for the structural optimization in future research on peptide therapeutics.

Graphical abstract