Broad-spectrum Antifolates for Treatment of Drug Resistant Bacillus anthracis

用于治疗耐药炭疽杆菌的广谱抗叶酸剂

• 批准号: 8289643
• 负责人: William W Barrow
• 金额: $ 84.29万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-02 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289643
• 关键词: Animal Model; Animals; Anthrax disease; Anti-Bacterial Agents; Antibiotics; Arts; Bacillus anthracis; Bacillus anthracis spore; Behavior; Berlin; Binding; Biochemistry; Biological Assay; Breathing; California; Carbon; Categories; Chemistry; Clinical; Collection; Complex; Computer Simulation; Crystallization; Crystallography; Custom; DHFR gene; Data; Development; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Discipline; Disease; Docking; Drug Combinations; Drug Delivery Systems; Drug Design; Drug resistance; Environment; Enzymes; Evaluation; Event; Folate; Folic Acid Antagonists; Free Energy; Generations; Goals; Health Sciences; Housing; Human; In Vitro; Infection; Infectious Agent; Inhibitory Concentration 50; Knowledge; Lead; Libraries; Life; Metabolic; Methodology; Methods; Microbiology; Modeling; Modification; Molecular; Molecular Biology; Morbidity - disease rate; Multi-Drug Resistance; Mus; National Institute of Allergy and Infectious Disease; New Mexico; Oklahoma; Parents; Pathway interactions; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Protein Chemistry; Publishing; Research; Research Institute; Research Personnel; Resistance; Science; Scientist; Screening procedure; Staging; Structure; Structure-Activity Relationship; System; Technology; Therapeutic; Time; Toxic effect; Trimethoprim; Universities; Update; Work; X ray diffraction analysis; X-Ray Diffraction; antimicrobial; bactericide; base; college; computerized data processing; cytotoxicity; design; diaminopyrimidine; drug development; drug discovery; economic impact; in vivo; inhibitor/antagonist; innovation; mortality; multidisciplinary; pathogen; pharmacophore; pre-clinical; prevent; product development; public health relevance; research study; resistance mechanism; resistant strain; respiratory; response; structural biology; three dimensional structure; tool; virtual

DESCRIPTION (provided by applicant): Inhalation anthrax is a life-threatening disease that would result from the release of Bacillus anthracis spores into the environment. The economic impact of such an event, which would be secondary only to the resulting morbidity and mortality figures, would be in the billions. Although approved antibiotics are available for use against anthrax, they represent standard classes currently being used for other diseases. Resistant strains of B. anthracis exist for certain antimicrobials and development of resistant strains to all the available drugs is achievable with current molecular tools. There is only one new antimicrobial in late-stage development that is effective in preventing inhalation anthrax infections. The goal of this R01 proposal is to develop a new assemblage of antimicrobials for the treatment of inhalation anthrax that will inhibit a critical metabolic enzyme, dihydrofolate reductase (DHFR). The anthracis DHFR is inherently resistant to the only clinical drug for this target. Thus, if multiple-resistant B. anthracis were covertly created, DHFR would likely be unchanged and these new antimicrobials would be effective against those strains. Through an R21, several new parent compounds were identified that inhibit B. anthracis through selective activity against the bacterial DHFR (IC50s of 46-100 nM) but not human DHFR (IC50s > 25,000 nM). This approach will involve a team of scientists from diverse disciplines, including biochemistry, microbiology & structural biology, in silico technology, protein chemistry, molecular biology, medicinal chemistry, and animal models. The application is a specific response to a RFA request to develop therapeutics for NIAID Category A, B, and C priority pathogens. This application will involve the following Milestones: Milestone 1: Synthesize 4 more parent compounds designed from crystallographic working model and from previous studies; Milestone 2: Propose 25 suggested 1st generation compounds using in silico drug design methods; Milestone 3: Begin PK and MTD studies; Milestone 4: Synthesize and assay 8 selected compounds from 1st generation derivatives; Milestone 5: Complete MTD/PK studies; Milestone 6: Evaluate 1st generation lead compounds for efficacy in mouse anthrax model; Milestone 7: Identify 1-3 lead compounds for preclinical development. This multidisciplinary effort will involve both academic and privately owned research organizations participating in a comprehensive team-based plan that will facilitate the advancement of a promising therapeutic through the product development pathway. The public health relevance is the development of a therapeutic countermeasure that will be effective against multidrug-resistant strains of anthrax.

描述(申请人提供)：吸入性炭疽病是一种威胁生命的疾病，它会因炭疽芽胞释放到环境中而导致。这种事件的经济影响将是数十亿美元，仅次于由此产生的发病率和死亡率数字。虽然批准的抗生素可用于治疗炭疽病，但它们代表了目前用于其他疾病的标准类别。炭疽杆菌对某些抗菌剂存在耐药株，利用现有的分子工具可以开发出对所有可用药物的耐药株。在后期开发中，只有一种新的抗菌剂能有效预防吸入性炭疽感染。这份R01提案的目标是开发一组新的抗菌药，用于治疗吸入性炭疽病，该药将抑制一种关键的代谢酶--二氢叶酸还原酶(DHFR)。炭疽DHFR对这一靶点的唯一临床药物具有固有的耐药性。因此，如果隐蔽地产生多重耐药炭疽杆菌，DHFR很可能不会改变，这些新的抗菌剂将对这些菌株有效。通过R21，鉴定了几种新的母体化合物，它们通过对细菌DHFR(IC50为46-100 NM)而不是人DHFR(IC50&GT；25,000 NM)具有选择性活性来抑制炭疽杆菌。这一方法将涉及来自不同学科的科学家团队，包括生物化学、微生物学和结构生物学，涉及硅技术、蛋白质化学、分子生物学、药物化学和动物模型。该申请是对RFA要求开发针对NIAID A、B和C类优先病原体的治疗方法的具体回应。这项应用将涉及以下里程碑：里程碑1：再合成4个根据结晶学工作模型和先前研究设计的母体化合物；里程碑2：提出25个建议用于硅胶药物设计方法的第一代化合物；里程碑3：开始PK和MTD研究；里程碑4：从第一代衍生物中合成并测定8种选定的化合物；里程碑5：完成MTD/PK研究；里程碑6：评估第一代先导化合物在小鼠炭疽病模型中的有效性；里程碑7：确定1-3个用于临床前开发的先导化合物。这一多学科的努力将包括学术和私人拥有的研究组织参与一个全面的基于团队的计划，该计划将通过产品开发途径促进有前途的治疗方法的进步。与公共卫生相关的是开发一种治疗对策，该对策将有效地对抗多药耐药炭疽菌株。