[4.3.1] Bicyclic FKBP ligands inhibit Legionella pneumophila infection by LpMip-dependent and LpMip independent mechanisms

Legionella pneumophila is the causative agent of Legionnaires’ disease, a serious form of pneumonia. Its macrophage infectiv-ity potentiator (Mip), a member of a highly conserved family of FK506-binding proteins, plays a major role in the prolifera-tion of the Gram-negative bacterium in host organisms. In this work, we test our library of >1000 FKBP-focused ligands for inhibition of LpMip. The [4.3.1]-bicyclic sulfonamide turned out as a highly preferred scaffold and provided the most potent LpMip 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 inhibi-tion of LpMip alone.