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<p>The growing concern over bacterial multidrug resistance has led to a heightened interest in antimicrobial peptides (AMPs) known for their strong efficacy, albeit with high toxicity. In order to retain the potent antibacterial activity of AMPs while minimizing their systemic toxicity, we introduce a conjugate strategy with selective infection-activatable and bacteria-targeting capabilities. A series of colistin prodrugs with well-defined structures were developed by attaching a reactive oxygen species-responsive phenylboronic acid linker to all amines of colistin, followed by covalent linkage to sugars through the reaction of boronic acid and a diol moiety. Among these prodrugs, a lactosyl-functionalized colistin prodrug, LaP-Col, was identified because of its minimal toxicity toward normal tissues and ability to target bacteria. It exhibits a maximum tolerated dose over 20 times greater than colistin and minimal nephrotoxicity. In a mouse model of bacterial pneumonia, intravenous administration of LaP-Col led to its accumulation in the infected lung. It effectively killed bacteria, significantly improving the therapeutic efficacy and mouse survival rates. Overall, this study presents a prodrug strategy that effectively reduces the inherent high toxicity of colistin and enhances its therapeutic targeting efficacy, which has promising implications for modifying other potent but toxic AMPs.</p>

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A conjugate strategy capable of targeting bacteria and selectively being activated at infection sites

  • 期刊论文

  • 发表日期：

    2025年5月14日

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  • Yuhao Zhang,
  • Yingxue Deng,
  • Chanjuan Su,
  • Kangxiu Wu,
  • Chengrun Li,
  • Juntao Wang,
  • Houbing Zhang,
  • Dong Luo,
  • Songyin Huang,
  • Liping Zhao,
  • Menghua Xiong,
  • Yan Bao

摘要

The growing concern over bacterial multidrug resistance has led to a heightened interest in antimicrobial peptides (AMPs) known for their strong efficacy, albeit with high toxicity. In order to retain the potent antibacterial activity of AMPs while minimizing their systemic toxicity, we introduce a conjugate strategy with selective infection-activatable and bacteria-targeting capabilities. A series of colistin prodrugs with well-defined structures were developed by attaching a reactive oxygen species-responsive phenylboronic acid linker to all amines of colistin, followed by covalent linkage to sugars through the reaction of boronic acid and a diol moiety. Among these prodrugs, a lactosyl-functionalized colistin prodrug, LaP-Col, was identified because of its minimal toxicity toward normal tissues and ability to target bacteria. It exhibits a maximum tolerated dose over 20 times greater than colistin and minimal nephrotoxicity. In a mouse model of bacterial pneumonia, intravenous administration of LaP-Col led to its accumulation in the infected lung. It effectively killed bacteria, significantly improving the therapeutic efficacy and mouse survival rates. Overall, this study presents a prodrug strategy that effectively reduces the inherent high toxicity of colistin and enhances its therapeutic targeting efficacy, which has promising implications for modifying other potent but toxic AMPs.