Since the seminal discovery in 1976 that established the association between Aggregatibacter actinomycetemcomitans (Aa) and molar/incisor pattern periodontitis (MIPP) in adolescents, extensive efforts have been made to define this pathogen’s molecular relationship with disease. Aa is present in healthy oral flora, colonizing above the gum-line. The transition from health to disease is reflected in a shift from this habitat to an area below the gum-line, to the subgingival niche, an area with less oxygen. This localization favors Aa as it is a facultative anaerobic gram-negative bacterium. Through the secretion of toxins, it suppresses host defense and creates a suitable environment for other pathogens. Our study examines the role of cytolethal distending toxin (Cdt), one of three toxins produced by Aggregatibacter actinomycetemcomitans (Aa), in MIPP. Cdt is a tri-perditious toxin with cell type-specific intoxication. The active Cdt subunit, CdtB acts as a phosphatidylinositol-3,4,5-triphosphate phosphatase leading to an imbalance in phosphatidylinositol (PI) pools. Previous studies have established the active CdtB subunit as modulating PI3K signaling event. Herein, we unravel another aspect of CdtB’s phosphoinositide phosphatase activity; the modulation of host cell phagosome maturation. We test the hypothesis that Aa Cdt-mediated disruption in macrophage phagosome processing leads to Aa survival contributing to disruption of local host defense. We found that AaCdt hijacks macrophage phagocytic function by depleting PIP3 pools and enhancing PI3,4P2 levels. On a molecular level, this increase in PI3,4P2, decreases Rab5-association with the maturing phagosomes leading to delayed phagosome maturation as detected by live cell confocal imaging. The specificity of delayed phagosome maturation as due to CdtB phosphatase activity was confirmed using a CdtB mutant lacking phosphatase activity. We show that Cdt –mediated delays in phagosome maturation contributed to Aa survival. Aa producing Cdt has a high association with MIPP, and previous studies have documented pro-inflammatory cytokine release upon Cdt treatment. It is well known that specific cytokines, IL-1 (both a and b), IL-6, IL-8, IL-17, and TNF-a, can increase osteoclastogenesis. Therefore, we examined if Cdt intoxication modulates osteoclastogenesis by using high PMA (100ng/ml) and conventional osteoclast differentiation cytokines (RANKL and M-CSF 50ng/ml each) to differentiate THP-1 monocyte into osteoclast. Herein, we demonstrate that Cdt (50ng/ml) intoxication during differentiation increased osteoclastogenesis as detected using TRAP+ staining, immunoblot of TRAP and Cathepsin K as well as quantification of multi-nucleated cells. Enhanced osteoclastogenesis was the result of Cdt B phosphatase activity. Lastly, we further show that a synthetic small molecule lignan, LGM2605, a potent free radical scavenger, antioxidant, and anti-inflammatory agent, decreases Cdt and Aa mediated pro-inflammatory cytokine release and mitigates enhanced osteoclastogenesis in vitro with 100uM of LGM2605. Collectively, these studies further our understanding of the mechanisms underlying the role of Cdt and Aa in the evasion of phagocytosis and early events in microbial dysbiosis. Moreover, we provide the foundation for a promising therapeutic strategy for MIPP; mitigating Aa’s effect on host response with a small molecule lignin.