Novel inhibitors of Erm methyltransferases from NMR and parallel synthesis

被引:95
作者
Hajduk, PJ [1 ]
Dinges, J [1 ]
Schkeryantz, JM [1 ]
Janowick, D [1 ]
Kaminski, M [1 ]
Tufano, M [1 ]
Augeri, DJ [1 ]
Petros, A [1 ]
Nienaber, V [1 ]
Zhong, P [1 ]
Hammond, R [1 ]
Coen, M [1 ]
Beutel, B [1 ]
Katz, L [1 ]
Fesik, SW [1 ]
机构
[1] Abbott Labs, Div Pharmaceut Discovery, Abbott Pk, IL 60064 USA
关键词
D O I
10.1021/jm990293a
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The Erm family of methyltransferases confers resistance to the macrolide-lincosamide-streptogramin type B (MLS) antibiotics through the methylation of 23S ribosomal RNA. Upon the methylation of RNA, the MLS antibiotics lose their ability to bind to the ribosome and exhibit their antibiotic activity. Using an NMR-based screen, we identified a series of triazine-containing compounds that bind weakly to ErmAM. These initial lead compounds were optimized by the parallel synthesis of a large number of analogues, resulting in compounds which inhibit the Erm-mediated methylation of rRNA in the low micromolar range. NMR and X-ray structures of enzyme/inhibitor complexes reveal that the inhibitors bind to the S-adenosylmethionine binding site on the Erm protein. These compounds represent novel methyltransferase inhibitors that serve as new leads for the reversal of Erm-mediated MLS antibiotic resistance.
引用
收藏
页码:3852 / 3859
页数:8
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