Kribellosides, novel RNA 5′-triphosphatase inhibitors from the rare actinomycete Kribbella sp. MI481-42F6

• Published in: Journal of antibiotics 2017-05, Vol.70 (5), p.582-589
• Main Authors: Igarashi, Masayuki, Sawa, Ryuichi, Yamasaki, Manabu, Hayashi, Chigusa, Umekita, Maya, Hatano, Masaki, Fujiwara, Toshinobu, Mizumoto, Kiyohisa, Nomoto, Akio
• Format: Article
• Language: English
• Subjects: 38/22; 38/23; 631/326/22/1292; 639/638/309/2144; Acid Anhydride Hydrolases - antagonists & inhibitors; Actinobacteria - metabolism; Actinomycetes; Antifungal activity; Antifungal Agents - administration & dosage; Antifungal Agents - isolation & purification; Antifungal Agents - pharmacology; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Capping; Drug development; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Ethers; Fungicides; Guanine; Inhibitory Concentration 50; Life Sciences; Medicinal Chemistry; Metabolites; Microbial Sensitivity Tests; Microbiology; mRNA; Organic Chemistry; original-article; Repressors; RNA modification; RNA triphosphatase; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - enzymology; Transcription; Triphosphatase; Yeast; Yeasts
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/ja.2016.161

Yeast capping enzymes differ greatly from those of mammalian, both structurally and mechanistically. Yeast-type capping enzyme repressors are therefore candidate antifungal drugs. The 5′-guanine-N7 cap structure of mRNAs are an essential feature of all eukaryotic organisms examined to date and is the first co-transcriptional modification of cellular pre-messenger RNA. Inhibitors of the RNA 5′-triphosphatase in yeast are likely to show fungicidal effects against pathogenic yeast such as Candida. We discovered a new RNA 5′-triphosphatase inhibitor, designated as the kribellosides, by screening metabolites from actinomycetes. Kribellosides belong to the alkyl glyceryl ethers. These novel compounds inhibit the activity of Cet1p (RNA 5′-triphosphatase) from Saccharomyces cerevisiae in vitro with IC 50 s of 5–8 μ M and show antifungal activity with MICs ranging from 3.12 to 100 μg ml −1 against S. cerevisiae.