G-quadruplex motifs in Neisseria gonorrhoeae as anti-gonococcal targets

Neisseria gonorrhoeae is an obligate human pathogen that causes gonorrhea and has shown a vast emergence of multidrug resistance in recent times. It is necessary to develop novel therapeutic strategies to combat this multidrug-resistant pathogen. The non-canonical stable secondary structures of nucleic acids, G-quadruplexes (GQs), are reported to regulate gene expressions in viruses, prokaryotes, and eukaryotes. Herein, we explored the whole genome of N. gonorrhoeae to mine evolutionary conserved GQ motifs. The Ng-GQs were highly enriched in the genes involved in various important biological and molecular processes of N. gonorrhoeae. Five of these GQ motifs were characterized using biophysical and biomolecular techniques. The GQ-specific ligand, BRACO-19, showed a high affinity towards these GQ motifs and stabilized them in both in vitro and in vivo conditions. The ligand showed potent anti-gonococcal activity and modulated the gene expression of the GQ-harboring genes. Strikingly, BRACO-19 also altered the biofilm formation in N. gonorrhoeae and its adhesion and invasion of the human cervical epithelial cells. In summary, the present study showed a significant role of GQ motifs in N. gonorrhoeae biology and put forward a step closer towards the search for therapeutic measures in combating the emerging antimicrobial resistance in the pathogen.

Automated summary

This study identified the significant role of G-quadruplexes (GQs) in N. gonorrhoeae, an obligate human pathogen that causes gonorrhea. Five GQ motifs in the N. gonorrhoeae genome were characterized and shown to be stabilized by the GQ-specific ligand, BRACO-19, in both in vitro and in vivo conditions. BRACO-19 exhibited potent anti-gonococcal activity and altered biofilm formation as well as the adhesion and invasion of human cervical epithelial cells by N. gonorrhoeae. This study advances the knowledge of N. gonorrhoeae biology and provides insights for developing therapeutic measures against this emerging antimicrobial resistant pathogen.