Improvement of Inhibitors of the Macrophage Infectivity Potentiator Protein from Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila – a Comparison

The treatment of Chagas disease and infections with Gram-negative bacteria is limited to a low number of antibiotics. Due to the development of resistance and partially severe side effects, there is an urgent need for new treatment strategies and virulence factors such as the macrophage infectivity potentiator (MIP) protein have emerged as a promising new therapeutic target. Inhibition of microbial MIP proteins leads to reduced viability and proliferation in pathogens such as Legionella pneumophila and Burkholderia pseudomallei. The parasitic pathogen of Chagas disease, Trypanosoma cruzi, also expresses a MIP protein, presumably involved in host cell invasion. Here, we took advantage of a compound library initially designed to inhibit MIPs of Burkholderia (BpMIP) and Legionella (LpMIP), to screen compounds against the Trypanosoma-MIP (TcMIP). Using a fluorescence polarization assay (FPA), the first qualitative structure-activity relationships could be derived. Further compound development led to highly active inhibitors of all tested MIPs from pathogenic microorganisms. Docking studies, molecular dynamics simulations and quantum mechanical calculations suggest an extended σ-hole of the meta-halogenated phenyl sulfonamide to be responsible for the high affinity.