The host calcium system contributes to intracellular pathogenesis.

Bacteria in the genus are obligate intracellular parasites of the eukaryotic cytoplasm. Pathogenic species are exquisitely evolved to only proliferate within eukaryotic host cells, particularly within endothelial cells of the mammalian vasculature. Through evolution in this very specific niche, have developed an inextricable dependence on multiple host functions. This absolute dependence on host cell biology offers a potential strategy for antibacterial development called host-targeted therapeutics. A previous screen of compounds that specifically target mammalian cell biology indicated that host-targeted calcium channel blockers (CCBs) inhibit proliferation within human cells. CCBs are routinely prescribed to human patients as antihypertensives or antianginals that function by disrupting the calcium ion equilibrium in vesicula/cardiac smooth muscle cells. To further investigate the potential anti- activities of CCBs, we sought to define the interaction between pathogenic and the host Ca system. Achieved data demonstrate that CCBs inhibit proliferation within endothelial cells, and that physical disruption of the host Ca ion gradient also disrupts growth. Additional analyses reveal that infection leads to a rapid and persistent disruption of the host Ca equilibrium. By querying pathogenesis, we demonstrate that some CCBs marginally disrupt rickettsial adherence to the host cell or induce apoptosis. However, all tested CCBs universally and significantly disrupt the ability of to polymerize actin. Together, these data demonstrate that CCBs possess anti- properties that function by disrupting rickettsial actin polymerization, and these results highlight the complex interdependence of and host cell biology.