Richard J Wall, Sandra Carvalho, Rachel Milne, Juan A. Bueren-Calabuig, Sonia Moniz, Juan Cantizani-Perez, Lorna MacLean, Albane Kessler, Ignacio Cotillo, Lalitha Sastry, Sujatha Manthri, Stephen Patterson, Fabio Zuccotto, Stephen Thompson, Julio J. Martín, Maria Marco, Timothy J. Miles, Manu De Rycker, Michael Thomas, Alan H. Fairlamb, Ian H. Gilbert, Susan Wyllie.
Available treatments for Chagas’ disease and visceral leishmaniasis are inadequate and there is a pressing need for new therapeutics. Drug discovery efforts for both diseases principally rely upon phenotypic screening. However, the optimisation of phenotypically-active compounds is hindered by a lack of information regarding their molecular target(s). To combat this issue we initiate target deconvolution studies at an early stage. Here, we describe comprehensive genetic and biochemical studies to determine the targets of three unrelated phenotypically-active compounds. All three structurally-diverse compounds target the Qi active-site of cytochrome b, part of the cytochrome bc1 complex of the electron transport chain. Our studies go on to identify the Qi site as a promiscuous drug target in Leishmania donovani and Trypanosoma cruzi with a propensity to rapidly mutate. Strategies to rapidly identify compounds acting via this mechanism are discussed to ensure drug discovery portfolios are not overwhelmed with inhibitors of a single target.