Targeting the PlsX/Y pathway for novel antimicrobials

靶向 PlsX/Y 途径的新型抗菌药物

基本信息

批准号：
7916838
负责人：
Richard E. Lee
金额：
$ 53.95万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-19 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7916838
关键词：
Active Sites Acyltransferase Adverse effects Affect Alternative Therapies Amides Anabolism Anthrax disease Anti-Bacterial Agents Antibiotic Prophylaxis Antibiotics Area B-Lymphocytes Bacillus anthracis Bacteria Biochemistry Biological Biological Assay Biological Availability Bioterrorism Characteristics Ciprofloxacin Data Development Disease Drug Design Drug Kinetics Engineering Ensure Enzymes Evaluation Event Feedback Fluoroquinolones Future Genes Genome Germination Glycerol Gram-Positive Bacteria Grant Homologous Gene In Vitro Lead Lipid Biochemistry Mediating Membrane Metabolic Metabolism Microbiology Oral Pathway interactions Penetration Peptide Hydrolases Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phospholipids Population Prodrugs Production Property Prophylactic treatment Proteins Reproduction spores Research Personnel Resistance Screening procedure Series Solubility Streptococcus pneumoniae Sulfonylurea Compounds Testing Vaccines Virulent Work aerosolized analog antimicrobial antimicrobial drug base cellular targeting cytotoxicity design drug discovery in vivo inhibitor/antagonist inorganic phosphate lipid metabolism mutant novel pathogen phosphonate

项目摘要

In an effort to develop new targets for antibacterial drug discovery, we recently discovered that Gram positive bacteria use a unique and essential pathway to synthesize their membrane phospholipids mediated by two gene products, PlsX and PlsY. This pathway generates a unique acyl-phosphate intermediate via PlsX that is then utilized as a substrate for PlsY. PlsY is an essential acyltransferase and there are no mammalian homologs. Using a bioisosteric approach we designed a number of nonhydrolyzable mimics of the acyl-phosphate intermediate. When tested against a panel of representative gram positive pathogens these compounds showed only modest antimicrobial activity, with the exception of B. anthracis (Sterne strain) that was potently inhibited. To confirm this result we then tested these compounds against a panel of virulent B. anthracis strains, all of which were highly sensitive to our best inhibitors yielding comparable MIC activity to existing antibiotics. We believe that this is an ideal starting point for the development of selective B. anthracis inhibitors, which will be explored in this grant. This study has 3 specific aims: (i) To synthesize an expanded set of inhibitors and to optimize the lead compounds with respect to anti-anthracis activity and for potential oral bioavailability; (ii) to biochemically evaluate the inhibition of the B. anthracis PlsY enzymes by the newly synthesized inhibitors; (iii) To perform a microbiological assessment on the emerging lead compounds, including testing for anti-B. anthracis activity. The end point of our studies will produce a better understanding of this important biological pathway and determine whether it is a suitable target for antibacterial drug discovery.

为了开发抗菌药物发现的新靶标，我们最近发现，革兰氏阳性细菌使用了独特而必不可少的途径来合成由两个基因产物PLSX和PLSY介导的膜磷脂。该途径通过PLSX产生独特的酰基磷酸磷酸磷酸盐中间体，然后用作PLSY的底物。 PLSY是必不可少的酰基转移酶，没有哺乳动物同源物。我们使用生物酶层次的方法设计了许多不可用的酰基磷酸酰基中间体的模仿。当针对一组代表性革兰氏阳性病原体进行测试时，这些化合物仅显示出适度的抗菌活性，除了受到有效抑制的炭疽芽孢杆菌（Sterne菌株）外。为了确认这一结果，我们随后针对毒性嗜血芽孢杆菌菌株对这些化合物进行了测试，这些化合物对我们的最佳抑制剂高度敏感，这些抑制剂与现有抗生素具有可比的MIC活性。我们认为，这是开发选择性B.炭疽病抑制剂的理想起点，这将在这笔赠款中进行探讨。这项研究具有3个特定目的：（i）合成一组扩展的抑制剂，并优化有关抗蒽活性和潜在口服生物利用度的铅化合物；（ii）通过生化评估新合成的抑制剂对炭疽芽孢杆菌PLSY酶的抑制；（iii）对新兴铅化合物进行微生物学评估，包括对抗B的测试。炭疽活动。我们研究的终点将使人们更好地了解这一重要的生物学途径，并确定它是否是抗菌药物发现的合适靶标。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acyl-sulfamates target the essential glycerol-phosphate acyltransferase (PlsY) in Gram-positive bacteria.

DOI：
10.1016/j.bmc.2012.06.029
发表时间：
2012-08-15
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Cherian PT;Yao J;Leonardi R;Maddox MM;Luna VA;Rock CO;Lee RE
通讯作者：
Lee RE

Discovery of novel bacterial elongation condensing enzyme inhibitors by virtual screening.

通过虚拟筛选发现新型细菌延伸缩合酶抑制剂。

DOI：
10.1016/j.bmcl.2014.03.033
发表时间：
2014
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Zheng,Zhong;Parsons,JoshuaB;Tangallapally,Rajendra;Zhang,Weixing;Rock,CharlesO;Lee,RichardE
通讯作者：
Lee,RichardE