Bioorganic mechanism of peptide antibiotics

描述（由申请人提供）：细菌对抗生素的耐药性严重限制了我们克服传染病的能力。在几乎所有医院获得性病原体-抗菌素组合中都出现了耐药性病例。很快，我们最严重的传染病威胁将无法治愈，因为我们的有效抗生素正在减少。Ramoplanins和Enduracidins构成了一个多肽抗生素家族，对革兰氏阳性细菌具有强大的广谱活性，包括耐甲氧西林金黄色葡萄球菌、耐万古霉素粪肠球菌（VRE）和耐头孢菌素肺炎链球菌这三种重要的机会性人类病原体。Ramoplanin和Enduracidin抑制细菌肽聚糖生物合成的转糖基化交联步骤，其复杂机制涉及到转糖基化酶底物脂质中间体II的捕获。在Aim 1中，我们试图确定Ramoplanin最近确定的次级机制的分子机制，抑制革兰氏阳性细菌的细胞壁蛋白锚定和生物膜发育。细胞壁蛋白锚定的抑制降低了毒力潜力，并导致形成持续感染的能力受损。在Aim 2中，我们将积极表征革兰氏阳性菌对Ramoplanin耐药的分子机制。最后，在目标3中，我们将使用溶液和固态核磁共振方法在溶液和膜环境中对Enduracidin和Enduracidin:：脂质II复合物进行结构分析。反过来，我们希望将所获得的知识应用于开发具有更好活性的替代抗生素，以抵抗由于耐药和毒性细菌表型引起的感染。

DESCRIPTION (provided by applicant): Bacterial resistance to antibiotics has seriously limited our capacity to overcome infectious disease. Cases of resistance have emerged in virtually all hospital-acquired pathogen-antimicrobial combinations. Soon our most serious infectious threats will be untreatable given our dwindling arsenal of effective antibiotics. Ramoplanins and Enduracidins comprise a family of peptide antibiotics with potent broad-spectrum activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium (VRE), and cephalosporin-resistant Streptococcus pneumonia, three important opportunistic human pathogens. Ramoplanin and Enduracidin inhibit the transglycosylation cross-linking step of bacterial peptidoglycan biosynthesis in a complex mechanism involving capture of the transglycosylase substrate, Lipid Intermediate II. In Aim 1 we seek to determine the molecular mechanisms of a recently identified secondary mechanism of Ramoplanin, inhibition of cell wall protein anchoring and biofilm development in Gram-positive bacteria. Inhibition of cell wall protein anchoring diminishes virulence potential and results in an impaired capacity to form persistent infections. In Aim 2 we will proactively characterize the molecular mechanisms of Ramoplanin resistance in Gram-positive bacteria. Lastly, in Aim 3 we will perform structural analyses of Enduracidin and the Enduracidin::Lipid II complex in solution and in membrane environments using solution and solid state NMR approaches. In turn, we hope to apply the knowledge gained to the development of alternative antibiotics with improved activity against infections due to resistant and virulent bacterial phenotypes.