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<p>Conjugative IncX plasmids are vital for spreading clinically significant antibiotic resistance genes. We identified key factors governing the conjugative process of IncX plasmids, the plasmid encoded activator PrfaH and inhibitor H-NS. Deletion of <i>prfaH</i> completely abolishes conjugative transfer, and the PrfaH binding site is an <i>ops</i>-like sequence located downstream of the <i>prfaH</i> promoter. We solved the crystal structure of PrfaH and identified the residues that likely mediate interactions with its target. The IncX3 plasmid-encoded H-NS inhibits conjugation by directly repressing PrfaH expression, while simultaneously enhancing host fitness. This tradeoff between plasmid conjugation and fitness is indispensable for plasmid persistence in nutrient-deprived environments. The presence of PrfaH paralogs in various antibiotic resistance plasmids suggests its fundamental role in regulating plasmid transfer. Our study not only elucidates the regulatory mechanisms behind the horizontal transfer of IncX plasmids but also highlights PrfaH as a potential target for strategies aimed at combating antimicrobial resistance.</p>

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Comprehensive analysis of Enterobacteriaceae IncX plasmids reveals robust conjugation regulators PrfaH, H-NS, and conjugation-fitness tradeoff

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月4日

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  • Jun Yang,
  • Yaoyao Lu,
  • Jingjing Yu,
  • Xinhong Cai,
  • Chengzhen Wang,
  • Luchao Lv,
  • Robert A. Moran,
  • Xilin Zhao,
  • Zhengyi Hu,
  • Mingzhen Deng,
  • Jian-Hua Liu

摘要

Conjugative IncX plasmids are vital for spreading clinically significant antibiotic resistance genes. We identified key factors governing the conjugative process of IncX plasmids, the plasmid encoded activator PrfaH and inhibitor H-NS. Deletion of prfaH completely abolishes conjugative transfer, and the PrfaH binding site is an ops-like sequence located downstream of the prfaH promoter. We solved the crystal structure of PrfaH and identified the residues that likely mediate interactions with its target. The IncX3 plasmid-encoded H-NS inhibits conjugation by directly repressing PrfaH expression, while simultaneously enhancing host fitness. This tradeoff between plasmid conjugation and fitness is indispensable for plasmid persistence in nutrient-deprived environments. The presence of PrfaH paralogs in various antibiotic resistance plasmids suggests its fundamental role in regulating plasmid transfer. Our study not only elucidates the regulatory mechanisms behind the horizontal transfer of IncX plasmids but also highlights PrfaH as a potential target for strategies aimed at combating antimicrobial resistance.