The AAA+ ATPase p97 as a novel parasite and tuberculosis drug target

The multifunctional AAA+ ATPase p97 is an unfoldase/segregase involved in various cellular processes and present in all kingdoms of life. In mammals and yeast, p97 functions upstream of the proteasome. Interestingly, proteasome inhibitors targeting pathogenic microorganisms display efficacy in overcoming drug-resistant strains. Homologues of p97 have been found in disease-causing parasites and mycobacteria. Here, we review the current knowledge on the structure, function, and conservation of p97 in pathogens. We discuss the potential of parasite and mycobacterial p97 as a drug target against these pathogens and explore strategies in designing novel inhibitors. A successful strategy for inhibiting pathogenic p97 should lead to effectively killing the pathogen, minimising toxic and off-target effects, and providing specificity to avoid interfering with human p97.