Functional analysis of the lipoglycodepsipeptide antibiotic ramoplanin

被引:55
作者
Cudic, P
Behenna, DC
Kranz, JK
Kruger, RG
Wand, AJ
Veklich, YI
Weisel, JW
McCafferty, DG [1 ]
机构
[1] Univ Penn, Sch Med, Johnson Res Fdn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA
来源
CHEMISTRY & BIOLOGY | 2002年 / 9卷 / 08期
关键词
D O I
10.1016/S1074-5521(02)00191-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The peptide antibiotic ramoplanin is highly effective against several drug-resistant gram-positive bacteria, including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), two important opportunistic human pathogens. Ramoplanin inhibits bacterial peptidoglycan (PG) biosynthesis by binding to Lipid intermediates I and II at a location different than the N-acyl-D-Ala-D-Ala dipeptide site targeted by vancomycin. Lipid I/II capture physically occludes these substrates from proper utilization by the late-stage PG biosynthesis enzymes MurG and the transglycosylases. Key structural features of ramoplanin responsible for antibiotic activity and PG molecular recognition have been discovered by antibiotic semisynthetic modification in conjunction with NMR analyses. These results help define a minimalist ramoplanin pharmacophore and introduce the possibility of generating ramoplanin-derived peptide or peptidomimetic antibiotics for use against VRE, MRSA, and related pathogens.
引用
收藏
页码:897 / 906
页数:10
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