Targeting Oral Pathogens with Salvia officinalis and Nigella sativa Supercritical CO2 Extracts: A Pharmacodynamic Approach and Three-Dimensional Checkerboard Synergy for Novel Dental Antimicrobials

<b>Background</b>: Oral infections such as dental caries and candidiasis are mediated by resilient biofilms, which are increasingly tolerant to conventional antimicrobials. This study investigated the antimicrobial and antibiofilm effects of <i>Salvia officinalis</i> and <i>Nigella sativa</i> CO₂ extracts against <i>Streptococcus mutans</i> and <i>Candida albicans</i>, with emphasis on synergistic interactions. <b>Methods</b>: Extracts were analyzed using gas chromatography-mass spectrometry analysis (GC-MS) and evaluated through planktonic MIC/MBC assays, time-kill kinetics, and biofilm models (MBIC/MBEC, biomass, metabolic activity). A novel three-dimensional checkerboard (3D-CB) and fractional inhibitory concentration index (FICI) approach was applied to optimize extract ratios, concentrations, and exposure times. <b>Results</b>: <i>S. officinalis</i> extract showed greater activity against <i>S. mutans</i> (MIC 256 mg/L; MBC 512 mg/L), while <i>N. sativa</i> was more effective against <i>C. albicans</i> (MIC 256 mg/L; MFC 512 mg/L). Both extracts reduced biofilm biomass and metabolic activity by over 70% at higher doses. Synergy was confirmed at ratios of 70:30 (<i>S. officinalis: N. sativa</i>) for <i>S. mutans</i> (FICI 0.38) and 40:60 for <i>C. albicans</i> (FICI 0.42). The achieved synergistic effect further decreased MBEC values fourfold and prolonged post-antibiotic effects. <b>Conclusions</b>: Synergistic <i>S. officinalis</i>-<i>N. sativa</i> formulations enhanced antimicrobial activity against oral pathogens in both planktonic and biofilm states, supporting their potential as next-generation dental antimicrobials.