by Franco CH, Warhurst DC, Bhattacharyya T, Au HYA, Le H, Giardini MA, Pascoalino BS, Torrecilhas AC, Romera LMD, Madeira RP, Schenkman S, Freitas-Junior LH, Chatelain E, Miles MA, Moraes CB. International Journal for Parasitology: Drugs and Drug Resistance 2020, doi: 10.1016/j.ijpddr.2020.06.001.
Summary: Antifungals posaconazole and E1224, a prodrug of ravuconazole, presented therapeutic failure in clinical trials for etiological treatment of Chagas disease. To better understand the mechanism of action and resistance to these CYP51 inhibitors, a clone of the T. cruzi Y strain was cultured under intermittent and increasing concentrations of ravuconazole until phenotypic stability was achieved. The ravuconazole-selected clone was less fit in vitro and in vivo compared to the wild-type parental clone and was more than 300-fold more tolerant to ravuconazole than the parental clone. A novel amino acid residue change was found in the TcCYP51 gene in the resistant clones. The structural effects of this, and of other previously described residue changes, were modelled to understand their impact on interaction with CYP51 inhibitors.
