Virulence-conferring siderophore biosynthesis inhibitors

赋予毒力的铁载体生物合成抑制剂

• 批准号: 7140500
• 负责人: LUIS E QUADRI
• 金额: $ 23.59万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140500
• 关键词: Mycobacterium tuberculosis; Yersinia pestis; adenosine monophosphate; antibacterial agents; bioterrorism /chemical warfare; cheminformatics; combinatorial chemistry; drug design /synthesis /production; microorganism metabolism; siderophores; virulence

DESCRIPTION (provided by applicant): Yersinia pestis (Yp), the causative agent of the plague (PL), and Mycobacterium tuberculosis (Mt), the etiologic agent of tuberculosis (TB), are pathogens with an important impact in both global and national public health. The Center for Disease Control and Prevention (CDC) has included Yp and multiple-drug resistant (MDR) Mt in categories A and C, respectively, of biological agents for public health preparedness against bioterrorism. The lack of suitable antibiotics to treat outbreaks of MDR PL and MDR TB resulting from natural emergence or bioterrorism is an alarming scenario. Counter-bioterrorism measures require the development of an arsenal of new antimicrobial drugs against conventional and unconventional targets in Yp and Mt. Most antibiotics in clinical use to treat TB target enzymes involved in protein, nucleic-acid, or cell-wall component synthesis, whereas PL is primarily treated with antibiotics that inhibit protein or DMA synthesis. Many lines of evidence indicate that iron acquisition systems based on iron-chelators, referred to as siderophores, are required for the virulence of these pathogens. In particular, Yp siderophore biosynthesis is one of the targets for the development of drugs for intervention and treatment of Yp infections indicated in the Counter-Bioterrorism Research Agenda of the NIAID for CDC Category A Agents. Organism-specific drugs that inhibit siderophore biosynthesis will have use as therapies, alone or in combination with other drugs, to treat infections with MDR Yp and Mt strains. The goal of this proposal is to find compounds that inhibit Yp and Mt siderophore biosynthesis. To achieve this goal, we will screen combinatorial compound libraries for inhibitors of selected siderophore biosynthesis enzymes and synthesized rationally designed mechanism-based inhibitors of such enzymes. The selected enzymes have no homologs in humans. The identified inhibitors will be characterized in cell free assays and evaluated as inhibitors of bacterial growth, siderophore biosynthesis, and iron uptake. The identified inhibitors, and the chemoinformation generated by their analysis, will constitute a base for the rational development of improved inhibitors of siderophore-mediated iron acquisition in Yp and Mt. These inhibitors represent a first step towards developing antimicrobials targeting such process. These antimicrobials will constitute a base for subsequent studies for the development of new drugs that, alone or in combination therapies, are anticipated to be useful in the treatment of MDR Yp and Mb infections.

描述(申请人提供)：鼠疫的病原体--鼠疫耶尔森氏菌(Yp)和结核分枝杆菌(Mt)--结核病的病原体--对全球和国家公共卫生都有重要影响。疾病控制和预防中心(CDC)已将yp和多药耐药(MDR)mt分别列入A类和C类生物制剂，用于公共卫生防范生物恐怖主义。缺乏适当的抗生素来治疗由自然出现或生物恐怖主义引起的耐多药PL和耐多药结核病暴发，这是一个令人震惊的情况。 反生物恐怖主义措施要求开发新的抗微生物药物武器库，以对抗《青年计划》和《千年发展目标》中的常规和非常规目标。临床上用于治疗结核病的大多数抗生素都是针对蛋白质、核酸或细胞壁成分合成的酶，而PL主要是用抑制蛋白质或DMA合成的抗生素治疗的。许多证据表明，以铁络合剂为基础的铁获取系统，被称为铁载体，是这些病原体毒力所必需的。特别是，YP型铁载体的生物合成是CDC A类药物的NIAID反恐研究议程中指出的用于干预和治疗YP型感染的药物开发的目标之一。抑制铁载体生物合成的生物体特异性药物将单独或与其他药物联合使用，作为治疗MDR yP和mt菌株感染的药物。这项建议的目标是找到抑制yP和mt铁载体生物合成的化合物。为了实现这一目标，我们将筛选选定的铁载体生物合成酶抑制剂的组合化合物文库，并合成设计合理的基于机理的此类酶抑制剂。所选的酶在人类中没有同源物。已确定的抑制剂将在无细胞分析中进行表征，并作为细菌生长、铁载体生物合成和铁摄取的抑制剂进行评估。 所识别的抑制剂及其分析产生的化学信息将构成合理开发铁载体介导的铁获取的改进抑制剂的基础。这些抑制剂是朝着开发针对这一过程的抗菌剂迈出的第一步。这些抗菌剂将构成后续研究的基础，以开发新的药物，这些药物单独或联合治疗有望在治疗MDR yP和Mb感染方面有用。