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.