Fig. 5: AN15368 is activated by a T. cruzi serine carboxypeptidase and targets CPSF3.
a,b, Overexpression of CPSF3 increases resistance to AN15368 (a) (CPSF3-OE: n = 3 biological replicates; WT: n = 2 biological replicates), as well as to related benzoxaboroles (b). All assays were carried out in intracellular amastigotes. c, Suppression of parasite mRNA relative to host cell (African green monkey (Vero)) mRNA by exposure to AN14353 as indicated by the decline in the fraction of sequence reads mappable to parasite genome relative to host cell genome (hpt, hours post-treatment). d, Engineered Asn to His mutation at amino acid position 232 of CPSF3 conveys resistance to AN15368 by intracellular amastigotes (n = 3 biological replicates). e, Disruption of CBPs leads to a 1,000× increased resistance to AN15368 in intracellular amastigotes (TcCBP KO: n = 3 biological replicates; WT: n = 2 biological replicates). f, Some AN15368 analogues lacking activity to intracellular T. cruzi (intra-) are effective killers of the T. congolense (extracellular) and T. cruzi extracellular amastigotes (extra-). Data are presented as mean ± s.e.m.
