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<p>Antibiotic resistance is a growing global health threat that risks the lives of millions. Among the resistance mechanisms, that mediated by metallo-β-lactamases is of particular concern as these bacterial enzymes dismantle most β-lactam antibiotics, which are our widest applied and cheapest to produce antibiotic agents. So far, no clinically applicable metallo-β-lactamase inhibitors are available. Aiming to adapt to structural variations, we introduce the inhibitor concept: dynamically chiral phosphonic acids. We demonstrate that they are straightforward to synthesize, penetrate bacterial membranes, inhibit the metallo-β-lactamase enzymes NDM-1, VIM-2 and GIM-1, and are non-toxic to human cells. Mimicking the transition state of β-lactam hydrolysis, they target the Zn ions of the metallo-β-lactamase active site. As a unique feature, both of their stereoisomers bind metallo-β-lactamases, which provides them unparalleled adaptability to the structural diversity of these enzymes, and may allow them to hamper bacteria’s ability for resistance development.</p>

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Dynamically chiral phosphonic acid-type metallo-β-lactamase inhibitors

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月19日

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  • Kinga Virág Gulyás,
  • Liping Zhou,
  • Daniel Salamonsen,
  • Andreas Prester,
  • Kim Bartels,
  • Robert Bosman,
  • Paul Haffke,
  • Jintian Li,
  • Viola Tamási,
  • Fritz Deufel,
  • Johannes Thoma,
  • Anna Andersson Rasmussen,
  • Miklós Csala,
  • Hanna-Kirsti Schroder Leiros,
  • Zhijian Xu,
  • Mikael Widersten,
  • Holger Rohde,
  • Eike C. Schulz,
  • Weiliang Zhu,
  • Máté Erdélyi

摘要

Antibiotic resistance is a growing global health threat that risks the lives of millions. Among the resistance mechanisms, that mediated by metallo-β-lactamases is of particular concern as these bacterial enzymes dismantle most β-lactam antibiotics, which are our widest applied and cheapest to produce antibiotic agents. So far, no clinically applicable metallo-β-lactamase inhibitors are available. Aiming to adapt to structural variations, we introduce the inhibitor concept: dynamically chiral phosphonic acids. We demonstrate that they are straightforward to synthesize, penetrate bacterial membranes, inhibit the metallo-β-lactamase enzymes NDM-1, VIM-2 and GIM-1, and are non-toxic to human cells. Mimicking the transition state of β-lactam hydrolysis, they target the Zn ions of the metallo-β-lactamase active site. As a unique feature, both of their stereoisomers bind metallo-β-lactamases, which provides them unparalleled adaptability to the structural diversity of these enzymes, and may allow them to hamper bacteria’s ability for resistance development.