Bioorganic mechanism of peptide antibiotics

描述(申请人提供)：细菌对抗生素的抗药性严重限制了我们战胜传染病的能力。几乎在所有医院获得性病原体-抗菌药组合中都出现了耐药病例。很快，我们最严重的传染病威胁将无法治愈，因为我们的有效抗菌素武器库正在减少。雷莫拉宁和耐拉菌素是一类对革兰氏阳性菌具有很强广谱活性的多肽抗生素家族，包括甲氧西林耐药金黄色葡萄球菌、万古霉素耐药屎肠球菌(VRE)和头孢菌素耐药肺炎链球菌，这是人类三种重要的机会致病菌。雷莫拉宁和耐拉西丁通过一种复杂的机制抑制细菌肽聚糖生物合成的转糖基化交联步骤，该机制涉及捕获转糖基酶底物脂类中间体II。在目标1中，我们试图确定雷莫拉宁最近发现的一个二级机制，即抑制革兰氏阳性菌细胞壁蛋白锚定和生物膜形成的分子机制。抑制细胞壁蛋白锚定会降低毒力潜力，并导致形成持续感染的能力受损。在目标2中，我们将主动研究革兰氏阳性细菌对拉莫拉宁耐药的分子机制。最后，在目标3中，我们将使用溶液和固体核磁共振方法在溶液和膜环境中对Endraacidin和Endraacidin：：Liped II络合物进行结构分析。反过来，我们希望将所获得的知识应用于开发替代抗生素，以提高由于耐药和毒力细菌表型而引起的感染的活性。

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.