Inhibition of the Yeast Cytochrome bc1 Complex by Ilicicolin H, a Novel Inhibitor That Acts at the Qn Site of the bc1 Complex

Abstract

Ilicicolin H is an antibiotic isolated from the "imperfect" fungus Cylindrocladium iliciola strain MFC-870. Ilicicolin inhibits mitochondrial respiration by inhibiting the cytochrome bc 1 complex. In order to identify the site of ilicicolin action within the bc 1 complex we have characterized the effects of ilicicolin on the cytochrome

Exploiting mitochondria as targets for the development of new antifungals

“…The in vitro mode-of-action of ilicicolin was nicely identified to the yeast cytochrome bc1 reductase of Complex III of the mitochondrial electron transport chain. [49][50][51] Activity of the mammalian enzyme was unaffected, indicating that the compound is fungal-specific. Depending upon the fungal species, MICs ranged from 0.04-1.56 mg/mL.…”

“…None of the compounds mentioned above target mitochondria except ilicicolin, discussed below. [49][50][51] Ilicicolin is a CIII fungal-specific inhibitor…”

Antifungal Spectrum, In Vivo Efficacy, and Structure–Activity Relationship of Ilicicolin H

“…However, compounds that retained the general molecular shape of ilicicolin H, for example, hydrazones 6−8 and corresponding pyrazoles 9−11, lost only 10−20-fold antifungal activity as compared to compounds with significant change in the molecular shape (e.g., 2−5), which lost >250-fold activity (Table S4 in the Supporting Information). It appears that the retention of the shape is not sufficient for the retention of the activity, for example, the oxadiazocine (12), oxime (13), and isoxazole (14) did not show any activity at 10000 ng/mL. The whole cell activity SAR and the fungal reductase activity SAR did not track well.…”

“…In contrast, antimycin showed no selectivity in this assay with IC 50 values of 0.5, 0.5, and 0.1 ng/mL, respectively, against C. albicans MY1055 and rat and rhesus NADH:cytochrome c oxidoreductase. Independent studies by Gutierrez et al 14 showed >70-fold selectivity for the yeast ubiquinol: cytochrome c reductase (S. cerevisiae) as compared to the bovine reductase (IC 50 = 87−108 ng/mL, 200−250 nM).…”

“…The syntheses of hydrazones (6−8), pyrazole (9−11), and oxadiazocine (12) were recently reported. 17 The oxime (13) and isoxazole (14) were prepared by reaction of 1 with hydroxyl amine at room temperature followed by heating with acetic acid. Both geometrical isomers of oxime and hydrazones were formed but did not show any difference in their activity; therefore, the data for only one of the isomer are shown.…”