Cudic Predrag, Kranz James K, Behenna Douglas C, Kruger Ryan G, Tadesse Hellina, Wand A Joshua, Veklich Yuri I, Weisel John W, McCafferty Dewey G
Johnson Research Foundation and the Department of Biochemistry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6059, USA.
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7384-9. doi: 10.1073/pnas.102192099.
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.
肽抗生素瑞莫拉宁通过中断由转糖基酶和MurG酶催化的后期膜相关糖基转移酶反应来抑制细菌肽聚糖（PG）生物合成。瑞莫拉宁的作用机制涉及隔离脂质锚定的PG生物合成中间体，从物理上阻止这些底物被这些酶正常利用。在本报告中，我们描述了瑞莫拉宁与PG生物合成中间体相互作用的首个分子水平细节。结合PG单体的化学剖析进行的核磁共振分析表明，瑞莫拉宁八肽D-Hpg-D-Orn-D-alloThr-Hpg-D-Hpg-alloThr-Phe-D-Orn识别MurNAc-Ala-γ-D-Glu焦磷酸，这是PG中能够进行高亲和力络合和形成原纤维的最小成分。因此，瑞莫拉宁识别的PG结合位点不同于万古霉素靶向的N-酰基-D-Ala-D-Ala部分。由于瑞莫拉宁在结构上比万古霉素等糖肽类抗生素更简单，源自该识别序列的拟肽类化疗药物未来可能用作抗万古霉素耐药性粪肠球菌、耐甲氧西林金黄色葡萄球菌及相关病原体的抗生素。
