FTR1335 is a novel synthetic inhibitor of Candida albicans N-myristoyltransferase with fungicidal activity.
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 (IC(50)) for CaNmt was 0.49 nM, which was much lower than the 5400 nM IC(50) 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 microM. These results indicate that FTR1335 might represent a novel family of Nmt inhibitors with fungicidal activity.
Ebara
Shinji
S
Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan.
Naito
Hiroyuki
H
Nakazawa
Kyoko
K
Ishii
Fumio
F
Nakamura
Masataka
M
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology*; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
C503070:(1R,3S)-N-(2-(cyclopeanthylcarbonyl) amino-benzothiazol-6-yl-3-(2-naphthylmethyl) amino)cyclohexanecarboxamide; D000935:Antifungal Agents; D052160:Benzothiazoles; D003510:Cyclohexanes; D013844:Thiazoles; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase