Complexation of peptidoglycan intermediates by the lipoglycodepsipeptide antibiotic ramoplanin: Minimal structural requirements for intermolecular complexation and fibril formation

被引:60
作者
Cudic, P
Kranz, JK
Behenna, DC
Kruger, RG
Tadesse, H
Wand, AJ
Veklich, YI
Weisel, JW
McCafferty, DG
机构
[1] Johnson Res Fdn, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Dept Biochem, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Dept Biophys, Philadelphia, PA 19104 USA
[4] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA
关键词
D O I
10.1073/pnas.102192099
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The peptide antibiotic ramoplanin inhibits bacterial peptidoglycan (PG) biosynthesis by interrupting late-stage membrane-associated glycosyltransferase reactions catalyzed by the transglycosylase and MurG enzymes. The mechanism of ramoplanin involves sequestration of lipid-anchored PG biosynthesis intermediates, physically occluding these substrates from proper utilization by these enzymes. In this report, we describe the first molecular-level details of the interaction of ramoplanin with PG biosynthesis intermediates. NMR analysis in conjunction with chemical dissection of the PG monomer revealed that the ramoplanin octapeptide D-Hpg-D-Orn-D-alloThr-Hpg-D-Hpg-alloThr-Phe-D-Orn recognizes MurNAc-Ala-gamma-D-Glu pyrophosphate, the minimum component of PG capable of high-affinity complexation and fibril formation. Ramoplanin therefore recognizes a PG binding locus different from the N-acyl-D-Ala-D-Ala moiety targeted by vancomycin. Because ramoplanin is structurally less complex than glycopeptide antibiotics such as vancomycin, peptidomimetic chemotherapeutics derived from this recognition sequence may find future use as antibiotics against vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and related pathogens.
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页码:7384 / 7389
页数:6
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