Background:
Neisseria gonorrhoeae has emerged as a critical global health threat due to the rapid rise of antimicrobial resistance and the near-exhaustion of effective therapeutic options. With ceftriaxone now representing the sole reliable treatment in many regions, the discovery of novel anti-gonococcal agents is a pressing research priority. In this study, we integrated computational structural biology with experimental microbiology to investigate metal–organic frameworks (MOFs) as potential therapeutics targeting penicillin-binding protein 2 (PBP2), a validated and essential gonococcal drug target.
Methods:
Nineteen structurally diverse MOFs were screened through in silico modelling using the crystal structure of N. gonorrhoeae PBP2 (PDB: 3EQU). Protein preparation, deep-learning–based active site prediction, and molecular docking identified three lead candidates—Fe-BDC-258445, Ni-BDC-638866, and Cu-BDC-687690—exhibiting favourable binding energies, stable coordination geometries, and multiple hydrogen-bond, hydrophobic, and metal–protein interactions within the PBP2 catalytic cavity. Structural and physicochemical characterization (FTIR, SEM, BET, XRD, TGA) further confirmed framework integrity and functional group suitability for protein binding.
Results:
Experimental validation was conducted using standard EUCAST agar diffusion assays against N. gonorrhoeae strain P9-17 and a CDC/FDA reference panel of ceftriaxone-reduced susceptibility isolates. Among all candidates, only the Cu-BDC MOF demonstrated reproducible bactericidal activity, producing clear dose-dependent zones of inhibition and effectively killing high-MIC isolates. No activity was observed for Fe-BDC or Ni-BDC MOFs even at 10 mg/mL. Importantly, Cu-BDC showed specificity towards N. gonorrhoeae, with no bactericidal effects on A. baumannii, E. coli, K. pneumoniae, or P. aeruginosa. Ion-leaching experiments confirmed that antimicrobial activity was not attributable to free copper ions alone. Transmission electron microscopy revealed Cu-BDC–induced loss of piliation, membrane disruption, and cytoplasmic leakage. Cytotoxicity testing using human Chang conjunctival epithelial cells demonstrated low toxicity across tested concentrations.
Conclusion:
Overall, this study identifies Cu-BDC as a promising and highly specific anti-gonococcal material, supported by both computational and experimental evidence. These findings highlight the translational potential of MOF-based nanomaterials as next-generation antimicrobial agents against drug-resistant N. gonorrhoeae.