Development of novel proteins synthesis inhibitors for MDR tuberculosis
耐多药结核病新型蛋白质合成抑制剂的开发
基本信息
- 批准号:8495235
- 负责人:
- 金额:$ 93.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-06 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AminoglycosidesAnti-Bacterial AgentsAntibioticsAntitubercular AgentsBacillus (bacterium)BacteriaBacterial InfectionsBacterial ProteinsBindingBinding SitesBiochemicalBiological AssayBiological AvailabilityBiological FactorsCapromycinCellsClinicalClinical TrialsComputer AssistedDataDevelopmentDrug DesignDrug KineticsDrug resistanceDrug resistance in tuberculosisEnsureEvaluationFutureFuture GenerationsGenerationsGeneticInfectionKanamycinLeadLinezolidMediatingModificationMolecularMolecular WeightMulti-Drug ResistanceMultidrug-Resistant TuberculosisMutagenesisMycobacterium tuberculosisNeisseria gonorrhoeaeOralOrganismPenetrationProdrugsProtein BiosynthesisProtein Synthesis InhibitionProtein Synthesis InhibitorsProtocols documentationPumpResearchResearch ProposalsResistanceRibosomesSeriesSerumSiteSpectinomycinStagingStreptomycinStructureTechniquesTestingTherapeutic AgentsTuberculosisanalogantimicrobialbasebeta-Lactam Resistancedesigndrug candidatedrug developmentdrug discoverydrug resistant bacteriagenome sequencingimprovedin vivomethicillin resistant Staphylococcus aureusmicrobialmycobacterialnovelpathogenresearch studysafety testingscaffoldtuberculosis drugsuptake
项目摘要
DESCRIPTION (provided by applicant): Due to the recent rise in multi-drug resistant organisms, we investigated the potential for developing existing validated natural product scaffolds to produce new semi synthetic antibiotics with more potent activity. We focused on the low molecular weight aminocyclitol spectinomycin as it: has been under studied; has a safe pharmacological profile; targets a ribosomal binding site highly conserved across bacterial pathogens, but separate from other aminoglycosides; is potent in cell free assays; is structurally tractable, allowing for advanced synthetic modification using structure based drug design techniques; has limited clinical use due to bacterial penetration and uptake issues. Several novel analogs were generated and screened against panels of both sensitive and drug resistant bacteria to find compounds with improved anti-bacterial activity. From these series, we discovered a novel class of anti-tuberculosis agents, the spectinamides. The most potent of our compounds demonstrate: excellent anti-tuberculosis activity; on target inhibition of protein synthesis in M. tuberculosis; no cross resistance to existing anti-tuberculosis drugs including those active at the ribosome (Streptomycin, Kanamycin, Capreomycin and Linezolid); good pharmacokinetic profiles including excellent serum and microsomal stability; and anti- tuberculosis activity in vivo. Preliminary results show that improved activity of spectinamides results in part from superior uptake into TB bacilli. We believe the spectinamides are an important discovery of a new chemotype that can be used for the treatment of drug resistant M. tuberculosis infections which we plan to expand and further develop through this collaborative research proposal in three research aims: (i) Compound development - computer aided drug design will be used in an iterative drug development cycle for the design and synthesis of spectinamides with high anti-tubercular potency; (ii) Mode of action - Molecular techniques, including whole genome sequencing, will be used to determine the genetic basis for the improved activity and uptake of the spectinamides against TB; biochemical assays will be used evaluate mode of action of lead compounds at the target level to ensure compounds that progress in our lead development cycle remain potent and selective for inhibition of bacterial protein synthesis; (iii) Lead development and characterization - Compounds synthesized will progress through three stages of tests that include microbial assessment, pharmacokinetic testing, toxicologic and in vivo efficacy experiments. After each stage, the data will be used in further design and synthesis cycles in aim 1 and the best compounds will be selected to move on to the next stage such that viable, well characterized drug candidates will emerge from this study. In this study we propose to develop a novel class of protein synthesis inhibitors to treat problematic multi-drug resistant tuberculosis infections. Compounds discovered in this study may also have the potential to treat other drug resistant bacterial diseases.
描述(由申请人提供):由于最近多重耐药生物的增加,我们研究了开发现有的经过验证的天然产物支架以生产具有更有效活性的新型半合成抗生素的潜力。我们重点关注低分子量氨基环醇大观霉素,因为它已经被研究;具有安全的药理学特征;靶向在细菌病原体中高度保守的核糖体结合位点,但与其他氨基糖苷分离;在无细胞分析中有效;结构易于处理,允许使用基于结构的药物设计技术进行高级合成修饰;由于细菌渗透和吸收问题,临床使用有限。产生了几种新的类似物,并对敏感和耐药细菌进行了筛选,以找到具有更好的抗菌活性的化合物。从这些系列中,我们发现了一类新的抗结核药物,奇观酰胺。我们最有效的化合物表现出:出色的抗结核活性;结核分枝杆菌蛋白合成靶抑制作用的研究对现有抗结核药物无交叉耐药,包括核糖体活性药物(链霉素、卡那霉素、卷曲霉素和利奈唑胺);良好的药代动力学特征,包括良好的血清和微粒体稳定性;并具有体内抗结核活性。初步结果表明,观酰胺活性的提高部分是由于结核菌对观酰胺的吸收能力较强。我们相信,spectinamide是一种新的化学型的重要发现,可用于治疗耐药结核分枝杆菌感染,我们计划通过这一合作研究提案在三个研究目标中扩大和进一步发展:(i)化合物开发-计算机辅助药物设计将在迭代药物开发周期中用于设计和合成具有高抗结核能力的spectinamide;(二)作用方式-将使用分子技术,包括全基因组测序,以确定提高抗结核菌胺的活性和吸收的遗传基础;生化分析将用于评估先导化合物在目标水平上的作用模式,以确保先导化合物在我们的先导开发周期中的进展对抑制细菌蛋白质合成保持有效和选择性;㈢先导物的开发和表征——合成的化合物将经过三个阶段的测试,包括微生物评估、药代动力学测试、毒理学和体内功效实验。在每个阶段之后,数据将用于aim 1的进一步设计和合成周期,并选择最佳化合物进入下一阶段,以便从本研究中产生可行的,具有良好特征的候选药物。在这项研究中,我们建议开发一类新的蛋白质合成抑制剂来治疗有问题的多重耐药结核感染。在这项研究中发现的化合物也可能具有治疗其他耐药细菌疾病的潜力。
项目成果
期刊论文数量(0)
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Richard E. Lee其他文献
EVALUATION OF GLYCEROL AND DIMETHYL SULFOXIDE FOR THE CRYOPRESERVATION OF SPERMATOZOA FROM THE WOOD FROG (RANA SYLVATICA)
甘油和二甲基亚砜对林蛙 (RANA SYLVATICA) 精子冷冻保存的评价
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
J. A. Mugnano;J. P. Costanzo;Sara G. Beesley;Richard E. Lee - 通讯作者:
Richard E. Lee
Carotid blood flow and pathogenesis of cerebral ischaemia
颈动脉血流与脑缺血的发病机制
- DOI:
10.1007/978-94-011-1848-4_35 - 发表时间:
1993 - 期刊:
- 影响因子:0
- 作者:
M. Aldoori;Richard E. Lee - 通讯作者:
Richard E. Lee
The Bulbar Conjunctival Vascular Bed in Normal Pregnancy
- DOI:
10.1016/s0002-9378(16)38683-5 - 发表时间:
1953-04-01 - 期刊:
- 影响因子:
- 作者:
Robert Landesman;Gordon Douglas;Georgene Dreishpoon;Richard E. Lee - 通讯作者:
Richard E. Lee
Ultrastructural effects of lethal freezing on brain, muscle and Malpighian tubules from freeze-tolerant larvae of the gall fly, Eurosta solidaginis.
致命冷冻对耐冻胆蝇幼虫脑、肌肉和马氏小管的超微结构影响。
- DOI:
10.1016/s0022-1910(96)00073-x - 发表时间:
1997 - 期刊:
- 影响因子:2.2
- 作者:
Stephen D Collins;A. Allenspach;Richard E. Lee - 通讯作者:
Richard E. Lee
An approach to combinatorial library generation of galactofuranose mimics as potential inhibitors of mycobacterial cell wall biosynthesis: Synthesis of a peptidomimetic of uridine 5′-diphosphogalactofuranose (UDP-Galf)
呋喃半乳糖模拟物作为分枝杆菌细胞壁生物合成潜在抑制剂的组合文库生成方法:尿苷 5′-二磷酸半乳呋喃糖肽模拟物的合成 (UDP-Galf)
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
Richard E. Lee;Martin D. Smith;L. Pickering;G. Fleet - 通讯作者:
G. Fleet
Richard E. Lee的其他文献
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{{ truncateString('Richard E. Lee', 18)}}的其他基金
Training in the Design and Development of Infectious Disease Therapeutics
传染病治疗药物设计和开发培训
- 批准号:
10617855 - 财政年份:2015
- 资助金额:
$ 93.65万 - 项目类别:
Training in the Design and Development of Infectious Disease Therapeutics
传染病治疗药物设计和开发培训
- 批准号:
10447715 - 财政年份:2015
- 资助金额:
$ 93.65万 - 项目类别:
Development of Aminospectinomycins for Biodefense
用于生物防御的氨基大观霉素的开发
- 批准号:
8860114 - 财政年份:2014
- 资助金额:
$ 93.65万 - 项目类别:
Development of Aminospectinomycins for Biodefense
用于生物防御的氨基大观霉素的开发
- 批准号:
9291410 - 财政年份:2014
- 资助金额:
$ 93.65万 - 项目类别:
Development of Aminospectinomycins for Biodefense
用于生物防御的氨基大观霉素的开发
- 批准号:
8693411 - 财政年份:2014
- 资助金额:
$ 93.65万 - 项目类别:
Development of novel proteins synthesis inhibitors for MDR tuberculosis
耐多药结核病新型蛋白质合成抑制剂的开发
- 批准号:
8305156 - 财政年份:2010
- 资助金额:
$ 93.65万 - 项目类别:
Development of novel proteins synthesis inhibitors for MDR tuberculosis
耐多药结核病新型蛋白质合成抑制剂的开发
- 批准号:
7989056 - 财政年份:2010
- 资助金额:
$ 93.65万 - 项目类别:
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New technologies for targeted delivery of anti-bacterial agents
抗菌药物靶向递送新技术
- 批准号:
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针对细菌磷酸酶的新型抗菌剂。
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