Exploiting structural variations in highly conserved mitochondrial complex III to develop antifungal agents.

Abstract

Respiratory Complex III aka cyt bc1 are validated targets for antibiotics and fungicides. However, agents targeting cyt bc1are often toxic to mammalian hosts, limiting their use in treating human infections. In this work, structural differences are revealed in cyt bc1 of different organisms, exposing potential vulnerabilities to pharmacological exploitation. Using the cyt bc1 from the photosynthetic bacterium Rhodobactersphaeroides (Rsbc1) and bovine mitochondria (Btbc1) as surrogates for fungal and mammalian enzymes, respectively, we identified novel compound as selective inhibitors of cyt bc1, with much greater affinity for Rsbc1. Importantly, these compounds show potent in vitro activity against some of the medically important and agricultural fungal pathogens, compared to currently available systemic fungicides, with low cytotoxicity in both cultured human cells and laboratory animals. This study provides an example for exploiting structural differences in evolutionarily conserved enzymes to develop antifungal drugs.