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<p>Carrion’s disease is endemic to the South American Andes and is characterized by fatal hemolytic anemia. This neglected tropical disease is caused by <i>Bartonella bacilliformis</i>, a fastidious and slow-growing pathogen difficult in genetic manipulation. In this study, we determine that porin A and α/β-hydrolase are both necessary and sufficient for hemolysis induced by <i>B. bacilliformis</i>. These genes are identified through a screen of a Tn5 transposon mutant library. Using markerless deletion mutagenesis, porin A and α/β-hydrolase deletion mutants are generated and functionally analyzed by hemolysis assays. In silico analyses predict conserved biological functions and three-dimensional structures of the identified proteins, with the α/β-hydrolase showing structural similarity to known lipases. Site-directed mutagenesis of the α/β-hydrolase active site demonstrates that the catalytic triad (Ser205, Asp267, His310) is essential for its hemolytic function. Screening of a phospholipase inhibitor library comprising 27 bioactive compounds identifies compound 48/80 as a potent inhibitor of hemolysis, with activity in the micromolar range. Unraveling the molecular mechanisms underlying Carrion’s disease may facilitate the future development of anti-virulence therapies, a promising strategy particularly in the context of increasing antibiotic resistance of <i>B. bacilliformis</i>.</p>

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Porin A and α/β-hydrolase are necessary and sufficient for hemolysis induced by Bartonella bacilliformis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Alexander A. Dichter,
  • Florian Winklmeier,
  • Diana Munteh,
  • Wibke Ballhorn,
  • Sabrina A. Becker,
  • Beate Averhoff,
  • Halvard Bonig,
  • Adrian Goldman,
  • Meritxell García-Quintanilla,
  • Luis Solis Cayo,
  • Pablo Tsukayama,
  • Volkhard A. J. Kempf

摘要

Carrion’s disease is endemic to the South American Andes and is characterized by fatal hemolytic anemia. This neglected tropical disease is caused by Bartonella bacilliformis, a fastidious and slow-growing pathogen difficult in genetic manipulation. In this study, we determine that porin A and α/β-hydrolase are both necessary and sufficient for hemolysis induced by B. bacilliformis. These genes are identified through a screen of a Tn5 transposon mutant library. Using markerless deletion mutagenesis, porin A and α/β-hydrolase deletion mutants are generated and functionally analyzed by hemolysis assays. In silico analyses predict conserved biological functions and three-dimensional structures of the identified proteins, with the α/β-hydrolase showing structural similarity to known lipases. Site-directed mutagenesis of the α/β-hydrolase active site demonstrates that the catalytic triad (Ser205, Asp267, His310) is essential for its hemolytic function. Screening of a phospholipase inhibitor library comprising 27 bioactive compounds identifies compound 48/80 as a potent inhibitor of hemolysis, with activity in the micromolar range. Unraveling the molecular mechanisms underlying Carrion’s disease may facilitate the future development of anti-virulence therapies, a promising strategy particularly in the context of increasing antibiotic resistance of B. bacilliformis.