by Ahmad R, Van den Kerkhof M, Leprohon P, Smiejkowska N, Wuyts E, Van Wielendaele P, Dufour S, Devos S, Baeza Garcia A, Braillard S, Mowbray CE, Maes L, Sterckx YG-J, Ouellette M, Caljon G. Nature communications 2026. doi:10.1038/s41467-026-78576-9
Summary: Aminopyrazoles are a promising series of antileishmanial compounds. Deconvolution of their mechanism of action could aid clinical development, however, this has been a challenge because successive drug exposure has failed to select for resistance. The authors of this manuscript used chemical mutagenesis combined with aminopyrazole selective pressure and whole genome sequencing to produce a panel of 28 resistant Leishmania Infantum lines. Increased resistance was associated with multiple independent mutations in the LINF_180011100 protein, which was confirmed using LINF_180011100 gene overexpression and CRISPR-Cas9 gene editing. A direct interaction between the lead compound and recombinantly produced LINF_180011100 FYVE Zn finger domain was demonstrated through a biophysical assay. This work formally validates LINF_180011100 as a drug target and resistance determinant for several aminopyrazole leads.
