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: 8685877
• 负责人: RICHARD A BUNCE
• 金额: $ 49.19万
• 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 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685877
• 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 Design; Drug Targeting; 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; 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; screening; 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（由申请人提供）：吸入炭疽是一种威胁生命的疾病，这可能是由于炭疽芽孢杆菌孢子释放到环境中所致。这种事件的经济影响仅次于由此产生的发病率和死亡率数字。尽管可用于针对炭疽的批准抗生素，但它们代表目前用于其他疾病的标准类。对于某些抗菌剂，存在炭疽芽孢杆菌的抗性菌株，并且使用当前的分子工具可以实现所有可用药物的抗性菌株。在晚期发育中只有一种新的抗菌剂可有效防止吸入炭疽感染。该R01提案的目的是开发一种新的抗菌剂组合，用于治疗吸入炭疽，该炭疽将抑制关键的代谢酶，二氢叶酸还原酶（DHFR）。炭疽DHFR天生对该靶标的唯一临床药物具有抗药性。因此，如果秘密地产生了多种抗炭疽芽孢杆菌，DHFR可能会保持不变，并且这些新的抗菌剂将有效地抵抗这些菌株。通过R21，通过选择性活性对细菌DHFR（46-100 nm的IC50s），但没有人类DHFR（IC50S> 25,000 nm）抑制炭疽芽孢杆菌。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，硅技术，蛋白质化学，分子生物学，药物化学和动物模型。该应用程序是对RFA请求的特定响应，以开发NIAID类别A，B和C优先病原体的治疗剂。该应用将涉及以下里程碑：里程碑1：合成4种由晶体学工作模型和以前的研究设计的母体化合物；里程碑2：提出25种建议使用硅药物设计方法中的第一代化合物；里程碑3：开始PK和MTD研究；里程碑4：合成和分析从第一代衍生物中选出的8种化合物；里程碑5：完整的MTD/PK研究；里程碑6：评估小鼠炭疽模型功效的第一代铅化合物；里程碑7：识别1-3种用于临床前开发的铅化合物。这项多学科的工作将涉及参加一项综合团队计划的学术研究组织和私人研究组织，该组织将促进通过产品开发途径提高有希望的治疗方法。公共卫生的相关性是一种治疗对策的发展，该治疗对策将有效抵抗抗炭疽的多种抗性菌株。

项目成果

The structure and competitive substrate inhibition of dihydrofolate reductase from Enterococcus faecalis reveal restrictions to cofactor docking.

• DOI: 10.1021/bi401104t
• 发表时间: 2014-02-25
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Bourne, Christina R.;Wakeham, Nancy;Webb, Nicole;Nammalwar, Baskar;Bunce, Richard A.;Berlin, K. Darrell;Barrow, William W.
• 通讯作者: Barrow, William W.

Synthesis and biological evaluation of 2,4-diaminopyrimidine-based antifolate drugs against Bacillus anthracis.

• DOI: 10.3390/molecules19033231
• 发表时间: 2014-03-17
• 期刊: Molecules (Basel, Switzerland)
• 作者: Nammalwar B;Muddala NP;Bourne CR;Henry M;Bourne PC;Bunce RA;Barrow EW;Berlin KD;Barrow WW
• 通讯作者: Barrow WW

Classifying compound mechanism of action for linking whole cell phenotypes to molecular targets.

• DOI: 10.1002/jmr.2174
• 发表时间: 2012-04
• 期刊: JOURNAL OF MOLECULAR RECOGNITION
• 影响因子: 2.7
• 作者: Bourne, Christina R.;Wakeham, Nancy;Bunce, Richard A.;Nammalwar, Baskar;Berlin, K. Darrell;Barrow, William W.
• 通讯作者: Barrow, William W.

Comparative Study of the Frech Catalyst with Two Conventional Catalysts in the Heck Synthesis of 2,4-Diaminopyrimidine-based Antibiotics.

• DOI: 10.1080/00304948.2013.743755
• 发表时间: 2013
• 期刊: Organic preparations and procedures international
• 影响因子: 1.5
• 作者: Nammalwar B;Bunce RA;Berlin KD;Bourne CR;Bourne PC;Barrow EW;Barrow WW
• 通讯作者: Barrow WW

Identification of novel potential antibiotics against Staphylococcus using structure-based drug screening targeting dihydrofolate reductase.

使用针对二氢叶酸还原酶的基于结构的药物筛选来鉴定针对葡萄球菌的新型潜在抗生素。

• DOI: 10.1021/ci400686d
• 发表时间: 2014
• 期刊: Journal of chemical information and modeling
• 影响因子: 5.6
• 作者: Kobayashi,Maiko;Kinjo,Tomohiro;Koseki,Yuji;Bourne,ChristinaR;Barrow,WilliamW;Aoki,Shunsuke
• 通讯作者: Aoki,Shunsuke