New Broad-Acting Cell Wall Antibiotics for Biodefense

用于生物防御的新型广效细胞壁抗生素

• 批准号: 7275925
• 负责人: Ania Knap
• 金额: $ 37.95万
• 依托单位: MAXTHERA, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275925
• 关键词: Amino Acid Sequence; Anabolism; Animal Model; Anthrax disease; Anti-Bacterial Agents; Antibiotics; Bacillus anthracis; Back; Biological Factors; Categories; Cell Line; Cell Wall; Cells; Chemicals; Class; Clinical; Commit; Diagnostic; Docking; Drug Design; Drug resistance; Engineering; Enzymes; Escherichia coli; Exhibits; Fosfomycin; Genes; Goals; Growth; Human; In Vitro; Infection; Inhibitory Concentration 50; Isoenzymes; Lead; Mammalian Cell; Modeling; Mus; Pathway interactions; Peptidoglycan; Pharmaceutical Preparations; Phase; Plague; Property; Quinazolines; Range; Research Personnel; Resistance; Risk; Sepsis; Series; Serum; Specificity; Structure; Structure-Activity Relationship; Testing; Toxic effect; Transferase; UDP-N-acetylglucosamine 1-carboxyvinyltransferase; Yersinia enterocolitica; Yersinia pestis; analog; base; biodefense; cost; falls; high throughput screening; in vivo; inhibitor/antagonist; intraperitoneal; novel; pathogen; programs; resistance mechanism

DESCRIPTION (provided by applicant): A bioterrorist arsenal is likely to include a broad spectrum of bacterial species including the Category A pathogens Yersinia pestis (plague), a Gram-negative species, and Bacillus anthracis (anthrax), a Gram-positive species. Broad-spectrum antibiotics are potentially the most valuable for biodefense because these agents can be used quickly even in the absence of confirmatory diagnostic identification of species and can be stockpiled more efficiently and at lower cost. The overall goal of this application is to identify new antibacterial agents useful for biodefense against a broad spectrum of species and a wide range of drug resistance mechanisms. In Phase I, we will focus on a novel chemical series that potently inhibits UDP-GlcNAc enolpyruvyl transferase (EPT), an essential, broadly conserved, bacterial-specific enzyme catalyzing the first committed step in peptidoglycan synthesis. We will optimize this inhibitor series through a focused application of rational and structure-based drug design to generate lead compounds that are effective in an in vivo infection model. The specific aims are to (1) optimize the potency of the new inhibitors on EPT from Y. pestis (Yp) and B. anthracis (Ba); (2) demonstrate target specificity and inhibition of growth or viability of natural and engineered surrogates of Yp and Ba; and (3) demonstrate in vivo efficacy of EPT inhibitors against Yp and Ba surrogates in animal models of infection as well as determine in vitro ADMET profiles for the lead compounds. In Phase II, we will optimize an in vivo validated lead to the status of a clinical candidate.

描述（由申请人提供）：生物恐怖主义的阿森纳很可能包括各种细菌种类，包括A类病原体鼠疫耶尔森氏菌（瘟疫），革兰氏阴性物种，革兰氏阴性菌和炭疽菌（炭疽菌）（炭疽菌），革兰氏阳性物种。广谱抗生素可能是生物污染最有价值的，因为即使在没有验证性诊断性鉴定物种的情况下，这些药物也可以迅速使用，并且可以更有效地以较低的成本储存。该应用的总体目标是确定针对多种物种和广泛的耐药性机制有用的新抗菌剂。在第一阶段，我们将重点放在一个新型的化学系列上，该系列有效抑制UDP-GLCNAC烯醇转移酶（EPT），这是一种必不可少的，广泛保守的细菌特异性酶，催化肽聚糖合成的第一步。我们将通过集中应用基于理性和结构的药物设计来优化该抑制剂系列，以产生在体内感染模型中有效的铅化合物。具体的目的是（1）优化Y. pestis（YP）和B.炭疽病（BA）的EPT上新抑制剂的效力； （2）证明YP和BA的天然和工程替代物的目标特异性以及抑制生长或生存能力； （3）证明了EPT抑制剂对感染动物模型中对YP和BA替代物的体内功效，并确定铅化合物的体外ADMET谱。在第二阶段，我们将优化经体验证的临床候选者状态的导致。