Addressing Virulence Factors as an Alternative Anti-infectious Treatment

Infectious diseases are a main cause of morbidity and mortality worldwide, especially due to increasing antibiotic resistance in almost all bacteria. Hence, the development of new drugs with new modes of action is of paramount importance. Alternative to the development of inhibitors of the bacterial protein and DNA synthesis, targeting virulence factor is an emerging strategy, as almost no evolutionary pressure is caused. Immunophilins, in particular the macrophage infectivity potentiator (Mip) protein, belonging to the superfamily of peptidyl-prolyl cis-trans isomerase (PPIase) enzymes, have been demonstrated to be necessary for virulence in a broad-spectrum of pathogens, especially of Gram-negative bacteria such as Burkholderia pseudomallei, Legionella pneumophila, Chlamydia trachomatis, Neisseria speciies, and Coxiella burnetti as well as Trypanmosoma cruzei. Compounds derived from the pipecolic moiety of Rapamicin are potent PPIase inhibitors and reduce the infectivity of each microorganism. Hence, they were used to develop MIP inhibitors of the above-mentioned microorganisms by means of structure-based design.