P. gingivalis-host interactions direct antibiotic adjuvants for periodontitis antimicrobial therapy

Porphyromonas gingivalis ( P. gingivalis ) invades host cells to evade antibiotics, driving the recurrence of periodontitis. However, current clinical treatment strategies remain ineffective in addressing this intracellular invasion by the bacteria. Here, we report a host-directed strategy that blocks bacterial invasion by targeting key host factors, including collagen I (using FT011), lipid rafts (using simvastatin), integrin β1 (using ATN-161), and FAK signaling (using YH-306). Inhibiting these targets significantly reduced P. gingivalis infection in human oral keratinocytes and periodontal ligament stem cells. Crucially, simvastatin restored the osteogenic ability of P. gingivalis -infected PDLSCs. These drugs subsequently functioned as effective antibiotic adjuvants. The combination of simvastatin or YH-306 with metronidazole, a standard-of-care antibiotic for periodontitis, exhibited potent synergistic effects, significantly eradicating intracellular bacteria at reduced antibiotic dosages. In a rat periodontitis model, simvastatin-metronidazole therapy yielded superior outcomes, significantly mitigating bacterial load, inflammation, and alveolar bone loss. The repurposing of clinically available drugs, such as simvastatin, as antibiotic adjuvants represents a promising, readily translatable therapeutic approach for periodontitis.