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<p>Antibiotic resistance is rapidly emerging as one of the most critical health threats, with resistant microorganisms progressively diminishing the effectiveness of established antibiotics. As a result, the development of therapeutic approaches that effectively target resistant pathogens is of utmost importance. In this study, we developed inhibitors for APH(2”)-IVa, a bacterial kinase conveying resistance to aminoglycoside antibiotics. Starting from a hit of a fragment-based screening, we explored the inhibitory motif by structure-based design, ultimately leading to a series of triazole analogues. Advanced analogues displayed promising ADME properties, emerging selectivity <i>vs</i> a panel of human kinases, permeability in both Gram-positive and Gram-negative bacteria, and a moderate antibiotic efficacy for clinical strains of <i>P. aeruginosa</i>. Taken together, our results suggest inhibition of bacterial kinases could be a promising option to reinstall the efficacy of aminoglycoside antibiotics.</p>

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Targeting bacterial kinases as a strategy to counteract antibiotic resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月4日

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  • Vanessa Buffa,
  • Julien Kowalewski,
  • Guoman Qi,
  • Robin Deutscher,
  • Matijas Cica,
  • Marion Richardoz,
  • Mathilde Tomaszczyk,
  • Andreas Krämer,
  • Stefan Knapp,
  • Catherine Dunyach-Remy,
  • Katharina Rox,
  • Jean-Francois Guichou,
  • Corinne Lionne,
  • Felix Hausch

摘要

Antibiotic resistance is rapidly emerging as one of the most critical health threats, with resistant microorganisms progressively diminishing the effectiveness of established antibiotics. As a result, the development of therapeutic approaches that effectively target resistant pathogens is of utmost importance. In this study, we developed inhibitors for APH(2”)-IVa, a bacterial kinase conveying resistance to aminoglycoside antibiotics. Starting from a hit of a fragment-based screening, we explored the inhibitory motif by structure-based design, ultimately leading to a series of triazole analogues. Advanced analogues displayed promising ADME properties, emerging selectivity vs a panel of human kinases, permeability in both Gram-positive and Gram-negative bacteria, and a moderate antibiotic efficacy for clinical strains of P. aeruginosa. Taken together, our results suggest inhibition of bacterial kinases could be a promising option to reinstall the efficacy of aminoglycoside antibiotics.