[4.3.1]Bicyclic FKBP Ligands Inhibit Legionella Pneumophila Infection by Lp Mip‐Dependent and Lp Mip‐Independent Mechanisms

Legionella pneumophila is the causative agent of Legionnaires’ disease, a serious form of pneumonia. Its macrophage infectivity potentiator (Mip), a member of a highly conserved family of FK506‐binding proteins (FKBPs), plays a major role in the proliferation of the gram‐negative bacterium in host organisms. In this work, we test our library of >1000 FKBP‐focused ligands for inhibition of Lp Mip. The [4.3.1]‐bicyclic sulfonamide turned out as a highly preferred scaffold and provided the most potent Lp Mip inhibitors known so far. Selected compounds were non‐toxic to human cells, displayed antibacterial activity and block bacterial proliferation in cellular infection‐assays as well as infectivity in human lung tissue explants. The results confirm [4.3.1]‐bicyclic sulfonamides as anti‐legionellal agents, although their anti‐infective properties cannot be explained by inhibition of Lp Mip alone.