FTR1335 Is a Novel Synthetic Inhibitor of Candida albicans N-Myristoyltransferase with Fungicidal Activity

抄録

Inhibitors of the fungal enzyme N-myristoyltransferase (Nmt) reduce fungal growth, as this enzyme is essential for viability. We found that a newly synthesized benzothiazole derivative, (1R,3S)-N-{2-[(cyclopeanthylcarbonyl) amino]-benzothiazol-6-yl}-3-[(2-naphthylmethyl) amino] cyclohexanecarboxamide (FTR1335), preferentially inhibited Candida albicans Nmt (CaNmt) in a dose-dependent manner. The 50% inhibitory concentration (IC₅₀) for CaNmt was 0.49 nM, which was much lower than the 5400 nM IC₅₀ for human Nmt (HsNmt1). The mode of CaNmt inhibition was competitive with the substrate peptide and non-competitive with myristoyl-CoA. Moreover, FTR1335 showed strong antifungal activity in vitro, and the minimum fungicidal concentration for C. albicans was 0.78 μM. These results indicate that FTR1335 might represent a novel family of Nmt inhibitors with fungicidal activity.