Virulence-conferring siderophore biosynthesis inhibitors

赋予毒力的铁载体生物合成抑制剂

• 批准号: 6970236
• 负责人: LUIS E QUADRI
• 金额: $ 21万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970236
• 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（由申请人提供）：鼠疫（PL）的病原体鼠疫耶尔森氏菌（Yp）和结核病（TB）的病原体结核分枝杆菌（Mt）是对全球和国家都有重要影响的病原体公共卫生。美国疾病控制与预防中心 (CDC) 已将 Yp 和多重耐药 (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。缺乏合适的抗生素来治疗自然出现或生物恐怖主义导致的耐多药PL和耐多药结核病的爆发是一个令人震惊的情况。 反恐措施需要针对 Yp 和 Mt 地区的常规和非常规目标开发一系列新的抗菌药物。临床上使用的大多数抗生素都用于治疗结核病，目标酶涉及蛋白质、核酸或细胞壁成分的合成，而PL 主要使用抑制蛋白质或 DMA 合成的抗生素进行治疗。许多证据表明，基于铁螯合剂（称为铁载体）的铁获取系统是这些病原体的毒力所必需的。特别是，Yp铁载体生物合成是NIAID针对CDC A类药物的反恐研究议程中指出的用于干预和治疗Yp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可单独或与其他药物联合用作疗法，以治疗 MDR Yp 和 Mt 菌株的感染。该提案的目标是寻找抑制 Yp 和 Mt 铁载体生物合成的化合物。为了实现这一目标，我们将筛选选定铁载体生物合成酶抑制剂的组合化合物库，并合成合理设计的基于机制的此类酶抑制剂。所选酶在人类中没有同源物。鉴定出的抑制剂将在无细胞测定中进行表征，并作为细菌生长、铁载体生物合成和铁吸收的抑制剂进行评估。 所鉴定的抑制剂以及通过其分析产生的化学信息将为合理开发 Yp 和 Mt 中铁载体介导的铁获取的改良抑制剂奠定基础。这些抑制剂代表了开发针对这一过程的抗菌药物的第一步。这些抗菌药物将为后续新药开发研究奠定基础，这些新药单独或联合治疗预计可用于治疗 MDR Yp 和 Mb 感染。