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（由申请人提供）：鼠疫（YP），鼠疫（PL）的病因（PL）和结核分枝杆菌（MT），结核病（TB）的病因（MT）是对全球和国家公共卫生的重要影响的病原体。疾病控制与预防中心（CDC）分别包括YP和抗多药物（MDR）MT，分别是A和C类，用于针对生物恐怖主义的公共卫生准备的生物学剂。由于自然出现或生物恐怖主义而导致的MDR PL和MDR TB的爆发缺乏合适的抗生素，这是一种令人震惊的情况。 反抗恐怖主义措施需要开发YP和MT中的常规和非常规靶标的新的抗微生物药物，以治疗涉及蛋白质，核酸或细胞 - 毛孔成分的蛋白质靶酶的大多数抗生素，以治疗与蛋白质蛋白质，细胞 - 酸性成分合成，而PL PL的蛋白质，而与抗生素合成。许多证据表明，这些病原体的毒力需要基于铁督剂（称为铁载体）的铁采集系统。特别是，YP铁载体生物合成是开发用于干预和治疗YP感染的药物的靶标之一，在抗氧化疾病人的反恐怖主义研究议程中指示了CDC A类代理。抑制铁载体生物合成的有机体特异性药物将用作单独或与其他药物结合的疗法，以治疗MDR YP和MT菌株的感染。该提案的目的是找到抑制YP和MT铁载体生物合成的化合物。为了实现这一目标，我们将筛选组合化合物库，以限制选定的铁载体生物合成酶的抑制剂，并合成基于合理设计的机制的这种酶的抑制剂。选定的酶在人类中没有同源物。确定的抑制剂将在无细胞测定中进行表征，并评估为细菌生长，铁载体生物合成和铁摄取的抑制剂。 确定的抑制剂以及通过其分析产生的化学信息将构成YP和MT中铁载体介导的铁的抑制剂合理发展的基础。这些抑制剂是发展针对此类过程的抗生素的第一步。这些抗微生物将构成随后研究的基础，用于开发新药，这些药物单独或联合疗法预计将有助于治疗MDR YP和MB感染。