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<p>Bacteria possess numerous defense systems against phage infections, which limit phage infectivity and pose challenges for phage therapy. This study aimed to engineer phages capable of evading these defense systems, using the Tmn defense system as a model. We identified an anti-Tmn protein in the ΦSMS22 phage from the <i>Dhillonvirus</i> genus that inhibits Tmn function in <i>Escherichia coli</i>. Introducing this gene into the Tmn-sensitive ΦKSS9 phage enabled it to evade Tmn immunity. Additionally, we found that a single mutation in the <i>nmad5</i> gene, a DNA modification enzyme in <i>Dhillonvirus</i>, prevented Tmn from sensing phage infection. By mutating the <i>nmad5</i> gene in the Tmn-sensitive <i>Dhillonvirus</i>, we demonstrated that engineering phages to evade bacterial sensing mechanisms is another viable strategy. These two phage engineering approaches—introducing anti-defense genes and mutating sensing-related genes—present a promising strategy for establishing effective phage therapy by neutralizing bacterial defense systems.</p>

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Phage engineering to overcome bacterial Tmn immunity in Dhillonvirus

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月22日

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  • Wakana Yamashita,
  • Kotaro Chihara,
  • Aa Haeruman Azam,
  • Kohei Kondo,
  • Shinjiro Ojima,
  • Azumi Tamura,
  • Matthew Imanaka,
  • Franklin L. Nobrega,
  • Yoshimasa Takahashi,
  • Koichi Watashi,
  • Satoshi Tsuneda,
  • Kotaro Kiga

摘要

Bacteria possess numerous defense systems against phage infections, which limit phage infectivity and pose challenges for phage therapy. This study aimed to engineer phages capable of evading these defense systems, using the Tmn defense system as a model. We identified an anti-Tmn protein in the ΦSMS22 phage from the Dhillonvirus genus that inhibits Tmn function in Escherichia coli. Introducing this gene into the Tmn-sensitive ΦKSS9 phage enabled it to evade Tmn immunity. Additionally, we found that a single mutation in the nmad5 gene, a DNA modification enzyme in Dhillonvirus, prevented Tmn from sensing phage infection. By mutating the nmad5 gene in the Tmn-sensitive Dhillonvirus, we demonstrated that engineering phages to evade bacterial sensing mechanisms is another viable strategy. These two phage engineering approaches—introducing anti-defense genes and mutating sensing-related genes—present a promising strategy for establishing effective phage therapy by neutralizing bacterial defense systems.