Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore-IIT Indore, Khandwa Road, Simrol, Indore, Madhya Pradesh, 453 552, India.
Gujarat Biotechnology University, Gandhinagar, 382355, India.
Appl Microbiol Biotechnol. 2023 Aug;107(16):5145-5159. doi: 10.1007/s00253-023-12646-6. Epub 2023 Jul 6.
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. KEY POINTS: •Neisseria gonorrhoeae genome is enriched in non-canonical nucleic acid structures-G-quadruplexes. •These G-quadruplexes might regulate bacterial growth, virulence, and pathogenesis. •G-quadruplex ligands inhibit biofilm formation, adhesion, and invasion of the gonococcus bacterium.
淋病奈瑟菌是一种专性人体病原体，可引起淋病，并且最近显示出广泛的多药耐药性。有必要开发新的治疗策略来对抗这种多药耐药病原体。非典型稳定的核酸二级结构，G-四链体（GQs），据报道可调节病毒、原核生物和真核生物中的基因表达。在此，我们探索了淋病奈瑟菌的全基因组，以挖掘进化上保守的 GQ 基序。Ng-GQs 在参与淋病奈瑟菌各种重要生物和分子过程的基因中高度富集。使用生物物理和生物分子技术对其中五个 GQ 基序进行了表征。GQ 特异性配体 BRACO-19 对这些 GQ 基序具有高亲和力，并在体外和体内条件下稳定它们。该配体表现出强大的抗淋病奈瑟菌活性，并调节携带 GQ 的基因的表达。引人注目的是，BRACO-19 还改变了淋病奈瑟菌的生物膜形成及其对人宫颈上皮细胞的粘附和侵袭。总之，本研究表明 GQ 基序在淋病奈瑟菌生物学中具有重要作用，并朝着寻找治疗措施以对抗病原体中新兴的抗微生物耐药性迈出了一步。 关键点： •淋病奈瑟菌基因组富含非典型核酸结构-G-四链体。 •这些 G-四链体可能调节细菌生长、毒力和发病机制。 •G-四链体配体抑制淋病奈瑟菌生物膜形成、粘附和侵袭。
