S-Nitrosothiols modulate Porphyromonas gingivalis virulence.

Porphyromonas gingivalis is the key etiological pathogen of periodontal disease, a chronic oral inflammatory condition that affects over 14% of the global population. P. gingivalis possesses several potent virulence factors-including gingipains, hemagglutinins, and fimbriae-that drive microbial dysbiosis. To restore homeostasis, nitric oxide (NO) is endogenously produced by immune cells to eliminate the infection, but disease persistence necessitates the use of therapeutic agents. The multiple antibacterial mechanisms of NO minimize the potential for antimicrobial resistance compared to traditional antibiotics, making exogenous NO delivery a potential attractive strategy for combating P. gingivalis. The objective of this study was to evaluate the effect of exogenous NO on the virulence of P. gingivalis, including NO's capacity to influence biofilm formation and dispersion, gingipain activity and production, invasion of host cells, and mitigation of immune responses. Nitric oxide effectively modulated the virulent behavior of anaerobic P. gingivalis via transnitrosylation and nitrosative stresses, reducing the pathogen's ability to form biofilms and gingipain activity. Within the anaerobic niche, NO exposure alters the pathogen's ability to export gingipains, thereby significantly reducing its potential to invade host cells and evade the immune system. This work highlights the therapeutic potential of exogenous NO as a promising therapeutic to alter periodontal disease through its multimodal effects on the virulence of P. gingivalis.