Dual antimicrobial mechanism of a synthetic retinoid targeting the outer membrane of Porphyromonas gingivalis

Most antibacterial agents currently used to treat periodontal disease are broad-spectrum, which may induce bacterial antibiotic resistance and exacerbate dysbiosis in the oral cavity. Prior efforts to develop antibiotics targeting P. gingivalis have failed because of its unique outer membrane barrier. Designing more effective and specific antimicrobial agents are essential to address this challenge. This study identified that CD1530 uniquely penetrate the outer membranes of P. gingivalis. Notably, CD1530 exists in neutral and anionic forms at physiologic pH. This abrogates the resistance of P. gingivalis to cationic membrane-active antimicrobial agents. Moreover, CD1530 inhibits different metabolic activities, causing energy depletion and bacterial death. These findings suggest that CD1530 may be useful for overcoming the physical barriers of the outer membrane of P. gingivalis. The present work provides valuable insights for the development of uncharged, membrane-targeting therapeutics to combat a broader range of bacterial infections.