Investigating the role of cytochrome bd oxidases in the antibacterial activity of madecassic acid and derivatives thereof

Natural products are valuable starting points for drug discovery, although individual modes of action are often difficult to pin down. Ursanes such as madecassic acid have been shown to have antibacterial properties, but a variety of mechanisms have been proposed. In this paper, we report previously uninvestigated activity against cytochrome bd oxidases which are only found in prokaryotes and are therefore promising new targets, using madecassic acid and a set of synthetically modified derivatives. Our work shows that madecassic acid and its derivatives can block activity of these enzymes, while phenotypic effects in membrane and whole organism assays are more complex, consistent with modulation of multiple pathways depending upon molecular structure. This provides a new route to ursane-based antibacterial action while highlighting the importance of chemical modifications in fine-tuning biological activity of natural products.