Upcycling polyethylene terephthalate waste into novel Klebsiella pneumoniae fimbrial adhesin inhibitors: Design, synthesis, and integrated computational and experimental evaluation for drug discovery.

Klebsiella pneumoniae is a major opportunistic pathogen associated with severe nosocomial infections, and its escalating antimicrobial resistance underscores the urgent need for new therapeutic strategies. Targeting fimbrial adhesin proteins, a critical virulence factors required for epithelial attachment and early biofilm establishment offers a promising anti-virulence approach to disrupt infection at its initial stages. In this study, we report the repurposing of polyethylene terephthalate (PET) waste as a sustainable source for drug discovery by designing, synthesizing, structurally confirming, and functionally evaluating a novel hydrazine-based compound, 2-hydrazineylidene-1,2-diphenylethan-1-one terephthalate (HDT). HDT was obtained through upcycling of PET waste via depolymerization into terephthalic acid, followed by condensation with benzil and hydrazine hydrate, and its chemical structure was validated using 1H/13C NMR, FT-IR, UV-Vis, and mass spectrometry. Molecular docking demonstrated strong affinity of HDT toward the K. pneumoniae fimbrial adhesin, with a binding energy of -8.90 kcal/mol, surpassing ciprofloxacin (-6.89 kcal/mol). Molecular dynamics simulations further supported the stability and compactness of the HDT-adhesin complex through RMSD, Rg, SASA, and RMSF analyses. In vitro antibacterial assays revealed dose-dependent inhibition, with a maximum zone of inhibition of 24.22 ± 0.18 mm at 100 μg/disc, approaching ciprofloxacin (26.33 ± 0.24 mm), and statistical analysis confirmed significant activity (p < 0.05). The computational and in vitro findings identify HDT as a promising PET-derived preliminary antibacterial lead candidate against Klebsiella pneumoniae. Molecular docking and molecular dynamics simulations suggest that HDT may interact with the fimbrial adhesin protein, indicating a potential anti-virulence mechanism that requires experimental validation. However, additional studies evaluating cytotoxicity, selectivity, biofilm inhibition, broader strain coverage, and in vivo efficacy are required before HDT can be considered a therapeutic candidate.