Broad-spectrum Antifolates for Treatment of Drug Resistant Bacillus anthracis

描述（由申请人提供）：吸入性炭疽是一种危及生命的疾病，由炭疽芽孢杆菌孢子释放到环境中引起。这一事件的经济影响将以数十亿计，仅次于由此产生的发病率和死亡率。虽然已批准的抗生素可用于对抗炭疽，但它们代表了目前用于其他疾病的标准类别。B.炭疽菌存在于某些抗菌剂中，并且利用目前的分子工具可以实现对所有可用药物的抗性菌株的开发。只有一种新的抗菌剂处于后期开发阶段，可有效预防吸入性炭疽感染。该R 01提案的目标是开发一种新的用于治疗吸入性炭疽的抗菌剂组合，其将抑制关键代谢酶二氢叶酸还原酶（DHFR）。炭疽菌DHFR本身对该靶标的唯一临床药物具有耐药性。因此，如果多重抗性B.炭疽菌是秘密产生的，DHFR可能不会改变，这些新的抗菌剂对这些菌株有效。通过R21，鉴定了几种新的抑制B的母体化合物。通过对细菌DHFR（IC 50为46-100 nM）而不是人DHFR（IC 50> 25，000 nM）的选择性活性来抑制炭疽。这种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，计算机技术，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请求的具体回应，以开发NIAID A、B和C类优先病原体的治疗药物。本申请将涉及以下里程碑：里程碑1：根据晶体学工作模型和先前研究设计的另外4种母体化合物;里程碑2：使用计算机模拟药物设计方法提出25种建议的第一代化合物;里程碑3：开始PK和MTD研究;里程碑4：合成并测定第一代衍生物中选定的8种化合物;里程碑5：完成MTD/PK研究;里程碑6：评价第一代先导化合物在小鼠炭疽模型中的疗效;里程碑7：确定1-3种先导化合物用于临床前开发。这一多学科的努力将涉及学术和私营研究组织参与一个全面的团队计划，这将有助于通过产品开发途径推进有前途的治疗。的

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