Selective Inhibitors of Bacterial t-RNA-(N1G37) Methyltransferase (TrmD) That Demonstrate Novel Ordering of the Lid Domain

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• 作者：Pamela J. Hill ; Ayome Abibi ; Robert Albert ; Beth Andrews ; Moriah M. Gagnon ; Ning Gao ; Tyler Grebe ; Laurel I. Hajec ; Jian Huang ; Stephania Livchak ; Sushmita D. Lahiri ; David C. McKinney ; Jason Thresher ; Hongming Wang ; Nelson Olivier ; Ed T. Buurman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 26, 2013
• 年：2013
• 卷：56
• 期：18
• 页码：7278-7288
• 全文大小：576K
• 年卷期：v.56,no.18(September 26, 2013)
• ISSN：1520-4804

文摘

The tRNA-(N¹G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.