Virulence-conferring siderophore biosynthesis inhibitors

描述（由申请人提供）：鼠疫耶尔森菌（Yp）是鼠疫（PL）的病原体，结核分枝杆菌（Mt）是结核病（TB）的病原体，是对全球和国家公共卫生具有重要影响的病原体。疾病控制和预防中心（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由自然出现或生物恐怖主义引起的MDR PL和MDR TB的爆发是一个令人担忧的情况。 反生物恐怖主义措施需要开发一个新的抗微生物药物库，以对付Yp和Mt的常规和非常规目标。临床上用于治疗TB的大多数抗生素靶向参与蛋白质、核酸或细胞壁组分合成的酶，而PL主要用抑制蛋白质或DMA合成的抗生素治疗。许多证据表明，铁的收购系统的基础上铁螯合剂，称为铁载体，需要这些病原体的毒力。特别地，Yp铁载体生物合成是用于开发用于干预和治疗Yp感染的药物的靶标之一，其在NIAID的CDC A类试剂的反生物恐怖主义研究议程中指出。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组合用作治疗MDR Yp和Mt菌株感染的疗法。该提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的抑制剂的组合化合物库，并合成合理设计的机制为基础的抑制剂，这样的酶。所选的酶在人类中没有同源物。将在无细胞试验中对鉴定的抑制剂进行表征，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价。 所确定的抑制剂，并通过其分析产生的化学信息，将构成一个合理的发展的铁载体介导的铁收购YP和山的抑制剂的基础。这些抑制剂代表了开发针对此类过程的抗菌剂的第一步。这些抗菌药物将构成后续研究的基础，用于开发单独或联合治疗的新药，预计可用于治疗MDR Yp和Mb感染。

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.