Neisseria gonorrhoeae, the causative agent of gonorrhoea, is a major global public health concern with an estimated 87–100 million new cases annually. The rapid emergence of antimicrobial resistance (AMR), including resistance to extended-spectrum cephalosporins, has significantly reduced available treatment options and underscores the urgent need for novel therapeutics. Antimicrobial peptides (AMPs) represent promising candidates due to their broad-spectrum activity and diverse mechanisms of action. In this study, we evaluated the bactericidal activity of four synthetic AMPs—Alliumin, CN-AMP1, Taromycin A, and VCP-VT1—against N. gonorrhoeae.
Using minimum bactericidal concentration (MBC) assays, all peptides demonstrated >90% killing of the laboratory strain P9-17 within 1 hour at 100 µM. Potency varied upon titration, with VCP-VT1 exhibiting the lowest MBC₉₀ (1.56 µM), followed by CN-AMP1 (6.25 µM), Alliumin (12.5 µM), and Taromycin A (50 µM). Notably, all AMPs maintained strong bactericidal activity across a wide range of bacterial inocula (10³–10⁸ CFU), indicating a limited inoculum effect. Time–kill analyses revealed rapid bactericidal kinetics, with VCP-VT1 displaying the fastest activity, achieving ~80% killing within 15 minutes at high concentration. Activity was further assessed against five multidrug-resistant clinical isolates from the CDC/FDA panel. At 100 µM, VCP-VT1 achieved >99% killing across all isolates, whereas the other peptides showed variable, isolate-dependent efficacy. At MBC₉₀ concentrations, bactericidal activity declined for Alliumin, CN-AMP1, and Taromycin A, while VCP-VT1 retained ≥50% killing across all isolates. In a human epithelial infection model, AMP efficacy was reduced, with VCP-VT1 achieving ~60% killing, while the other peptides exhibited limited activity (12–30%). In contrast, ceftriaxone remained highly effective (>99% killing), highlighting challenges associated with peptide activity in complex biological environments.
Overall, these findings identify VCP-VT1 as a promising lead AMP with potent, rapid, and relatively robust activity against N. gonorrhoeae, including resistant strains. However, reduced efficacy under host-associated conditions emphasises the need for optimisation to improve stability and bioavailability in physiologically relevant settings.