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<p>The rapid emergence of multidrug-resistant (MDR) Gram-negative pathogens, particularly <i>Pseudomonas aeruginosa</i>, necessitates the development of antibacterial agents with novel mechanisms of action and improved delivery strategies. In this study, a minimalistic scaffold-hopping approach was employed to design pyrazolone- and imidazolone-based FabF (KAS II) inhibitors, followed by nanoformulation using Chit/PMMA nanogels to enhance antibacterial performance. Among the synthesized compounds, HAN3 exhibited the most potent intrinsic activity against Gram-negative bacteria and was further optimized through nanogel encapsulation. The resulting HAN3-Ng demonstrated markedly improved antibacterial efficacy against <i>P. aeruginosa</i>, with a significant reduction in MIC and enhanced FabF (KAS II) inhibition (IC₅₀ = 1.84 ± 0.05&#xa0;µg/mL), approaching the activity of the reference inhibitor cerulenin. HAN3-Ng also showed pronounced antibiofilm activity (up to 70.99% inhibition) and rapid, concentration-dependent bactericidal effects in time–kill assays, achieving sustained ≥ 3 log₁₀ CFU/mL reduction without bacterial regrowth. Molecular docking revealed that HAN3 occupies the FabF active site in a binding mode comparable to the co-crystallized ligand BHBA, involving Mg²⁺ coordination, hydrogen bonding with Arg87, and additional aromatic stabilization, supporting FabF as a primary intracellular target. Furthermore, nanogel formulations exhibited improved biocompatibility toward normal fibroblast cells relative to free compounds. Collectively, these findings demonstrate that nanoencapsulation substantially amplifies FabF-targeted antibacterial activity and biofilm suppression, positioning HAN3-Ng as a promising lead candidate for the treatment of <i>P. aeruginosa</i> infections and highlighting potential FabF (KAS II) nanotherapeutics as a viable strategy against Gram-negative resistance. These findings suggest that the synthesized compounds may act as potential FabF inhibitors, although further cellular target-validation studies are required to conclusively confirm FabF as the primary intracellular target.</p>

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Minimalistic Design and Nanoformulation of Pyrazolone and Imidazolone Analogs as Potent FabF (KAS II) Inhibitors for Combating Pseudomonas Aeruginosa Infection

  • 期刊论文

  • 发表日期：

    2026年6月25日

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  • Mohammed Almaghrabi,
  • Shaimaa Hussein,
  • Safaa A. Turkistani,
  • Arafa Musa,
  • Raed Alghamdi,
  • Tawfiq N. Juraybi,
  • Magdi E. A. Zaki,
  • Waad A. Samman,
  • Sobhi M. Gomha,
  • Saeed M. Tayeb,
  • Mohammed S. Abdulrahman,
  • Hany E. A. Ahmed

摘要

The rapid emergence of multidrug-resistant (MDR) Gram-negative pathogens, particularly Pseudomonas aeruginosa, necessitates the development of antibacterial agents with novel mechanisms of action and improved delivery strategies. In this study, a minimalistic scaffold-hopping approach was employed to design pyrazolone- and imidazolone-based FabF (KAS II) inhibitors, followed by nanoformulation using Chit/PMMA nanogels to enhance antibacterial performance. Among the synthesized compounds, HAN3 exhibited the most potent intrinsic activity against Gram-negative bacteria and was further optimized through nanogel encapsulation. The resulting HAN3-Ng demonstrated markedly improved antibacterial efficacy against P. aeruginosa, with a significant reduction in MIC and enhanced FabF (KAS II) inhibition (IC₅₀ = 1.84 ± 0.05 µg/mL), approaching the activity of the reference inhibitor cerulenin. HAN3-Ng also showed pronounced antibiofilm activity (up to 70.99% inhibition) and rapid, concentration-dependent bactericidal effects in time–kill assays, achieving sustained ≥ 3 log₁₀ CFU/mL reduction without bacterial regrowth. Molecular docking revealed that HAN3 occupies the FabF active site in a binding mode comparable to the co-crystallized ligand BHBA, involving Mg²⁺ coordination, hydrogen bonding with Arg87, and additional aromatic stabilization, supporting FabF as a primary intracellular target. Furthermore, nanogel formulations exhibited improved biocompatibility toward normal fibroblast cells relative to free compounds. Collectively, these findings demonstrate that nanoencapsulation substantially amplifies FabF-targeted antibacterial activity and biofilm suppression, positioning HAN3-Ng as a promising lead candidate for the treatment of P. aeruginosa infections and highlighting potential FabF (KAS II) nanotherapeutics as a viable strategy against Gram-negative resistance. These findings suggest that the synthesized compounds may act as potential FabF inhibitors, although further cellular target-validation studies are required to conclusively confirm FabF as the primary intracellular target.