Targeting the PlsX/Y pathway for novel antimicrobials

靶向 PlsX/Y 途径的新型抗菌药物

• 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
• 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

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独特且重要的途径来合成由两种基因产物 PlsX 和 PlsY 介导的膜磷脂。该途径通过 PlsX 生成独特的酰基磷酸中间体，然后将其用作 PlsY 的底物。 PlsY 是一种必需的酰基转移酶，没有哺乳动物同源物。使用生物等排方法，我们设计了许多不可水解的酰基磷酸中间体的模拟物。当针对一组代表性革兰氏阳性病原体进行测试时，这些化合物仅表现出适度的抗菌活性，但炭疽芽孢杆菌（斯特恩菌株）除外，其被有效抑制。为了证实这一结果，我们随后针对一组剧毒炭疽芽孢杆菌菌株测试了这些化合物，所有这些菌株都对我们最好的抑制剂高度敏感，产生与现有抗生素相当的 MIC 活性。我们相信，这是开发选择性炭疽杆菌抑制剂的理想起点，本次拨款将对此进行探索。这项研究有 3 个具体目标：(i) 合成一组扩展的抑制剂，并优化先导化合物的抗炭疽活性和潜在的口服生物利用度； (ii)通过生化评估新合成的抑制剂对炭疽芽孢杆菌PlsY酶的抑制作用； (iii) 对新出现的先导化合物进行微生物学评估，包括抗 B 菌测试。炭疽活动。我们研究的终点将有助于更好地理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点。

项目成果

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。

• 发表时间: 2014-06-01
• 影响因子: 2.7
• 作者: Zheng, Zhong;Parsons, Joshua B;Tangallapally, Rajendra;Zhang, Weixing;Rock, Charles O;Lee, Richard E
• 通讯作者: Lee, Richard E

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

酰基氨基磺酸盐靶向革兰氏阳性菌中必需的磷酸甘油酰基转移酶 (PlsY)。

• 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