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<p>The accelerating emergence of multidrug-resistant (MDR) bacteria and the declining efficacy of conventional antibiotics have renewed global interest in bacteriophage lysins as precision antibacterial agents. These muralytic enzymes, composed of modular catalytic and binding domains, enable targeted peptidoglycan degradation and provide a versatile molecular framework for next-generation antimicrobial design. When applied exogenously, recombinant lysins exhibit ultrafast bactericidal activity against Gram-positive bacteria and, through engineered membrane-permeabilizing elements, have been adapted to target MDR Gram-negative pathogens. Integrative experimental and computational advances, including high-resolution microscopy, membrane-probe assays, multi-omics profiling, and molecular dynamics (MD) simulations, have deepened mechanistic understanding of lysin–cell envelope interactions and informed rational protein engineering. Structure-guided optimization strategies now encompass domain recombination, antimicrobial peptide fusion, and pharmacokinetic stabilization via PEGylation, PASylation, or Fc/albumin conjugation, while complementary efforts in epitope depletion, and AI-assisted deimmunization enhance safety and re-administrability. Lysins combine exceptional target specificity, rapid and potent killing kinetics, low resistance potential, and favorable safety and synergistic profiles with conventional antimicrobials. Their expanding applications—from clinical therapeutics to food safety, agriculture, and animal husbandry—highlight their versatility as effective, environmentally benign biocontrol agents. Collectively, these advances mark the evolution of lysins from naturally occurring bacteriophage enzymes to engineered biologics, positioning them as a promising frontier in the fight against antimicrobial resistance.</p>

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Bacteriophage Lysins as Programmable Antimicrobials: Mechanisms, Engineering, and Translational Advances

  • 期刊论文

  • 发表日期：

    2026年3月13日

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  • Wenxin Ma,
  • Yan Lei,
  • Luyao Wang,
  • Yingtong Chen,
  • Min Ma,
  • Xia Chen

摘要

The accelerating emergence of multidrug-resistant (MDR) bacteria and the declining efficacy of conventional antibiotics have renewed global interest in bacteriophage lysins as precision antibacterial agents. These muralytic enzymes, composed of modular catalytic and binding domains, enable targeted peptidoglycan degradation and provide a versatile molecular framework for next-generation antimicrobial design. When applied exogenously, recombinant lysins exhibit ultrafast bactericidal activity against Gram-positive bacteria and, through engineered membrane-permeabilizing elements, have been adapted to target MDR Gram-negative pathogens. Integrative experimental and computational advances, including high-resolution microscopy, membrane-probe assays, multi-omics profiling, and molecular dynamics (MD) simulations, have deepened mechanistic understanding of lysin–cell envelope interactions and informed rational protein engineering. Structure-guided optimization strategies now encompass domain recombination, antimicrobial peptide fusion, and pharmacokinetic stabilization via PEGylation, PASylation, or Fc/albumin conjugation, while complementary efforts in epitope depletion, and AI-assisted deimmunization enhance safety and re-administrability. Lysins combine exceptional target specificity, rapid and potent killing kinetics, low resistance potential, and favorable safety and synergistic profiles with conventional antimicrobials. Their expanding applications—from clinical therapeutics to food safety, agriculture, and animal husbandry—highlight their versatility as effective, environmentally benign biocontrol agents. Collectively, these advances mark the evolution of lysins from naturally occurring bacteriophage enzymes to engineered biologics, positioning them as a promising frontier in the fight against antimicrobial resistance.