Deconvoluting the mode of action of antileishmanial aminopyrazoles through chemical mutagenesis

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.

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