Development of Aminospectinomycins for Biodefense
用于生物防御的氨基大观霉素的开发
基本信息
- 批准号:9291410
- 负责人:
- 金额:$ 69.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-06-04 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAminoglycosidesAnti-Bacterial AgentsAntibioticsBacterial InfectionsBacterial ProteinsBindingBiochemicalBiological AssayCellsChemicalsClinicalClinical TrialsComputer AssistedDataDevelopmentDrug DesignDrug KineticsDrug resistanceEnsureEnzymesEvaluationFutureFuture GenerationsGenerationsGenetic TranscriptionIn VitroInfectionLeadMedicalModificationMolecular WeightMulti-Drug ResistanceNational Institute of Allergy and Infectious DiseaseNatural ProductsNeisseria gonorrhoeaeOrganismPharmaceutical PreparationsPharmacologyPositioning AttributePreclinical TestingPredispositionPropertyProtein BiosynthesisProtein InhibitionProtein Synthesis InhibitionResearch PersonnelResistanceRibosomal ProteinsRibosomesRouteSafetySeriesSerumSiteSpectinomycinStreptococcus pneumoniaeStructureTestingToxicologyWorkanalogantimicrobialantimicrobial drugbacterial resistancebasebiodefensechemical stabilitycommercializationdesigndrug candidatedrug developmentdrug discoveryexperienceexperimental studyimprovedin vitro activityin vivoneglectnovelpathogenpreclinical developmentpublic health relevanceresistance mechanismsafety testingscaffold
项目摘要
DESCRIPTION (provided by applicant): Numerically, the most successful strategy in antibacterial drug discovery has been the synthetic modification of natural products to produce new semisynthetic antibiotics. However, this approach has only been successfully applied to a few select scaffolds. Revisiting this approach, we have focused on examining the low molecular weight antibiotic spectinomycin, which we felt had been neglected, in spite of its safe pharmacological profile. Spectinomycin is an aminocyclitol antibiotic that specifically inhibits bacterial protein synthesis by binding to 30S ribosome at a unique site that is highly conserved across bacterial pathogens. Although, spectinomycin is potent in cell free assays its clinical use it restricted to second line treatment for Neisseria gonorrhoeae infections. Previous attempts to develop spectinomycin analogs, in the 1980s, led to the discovery of trospectinomycin, which showed improved activity against different bacterial pathogens and progressed into late stage clinical trials before being withdrawn for commercial reasons, validating the potential to modify this core to obtain more potent generations of drug. In view of the recent rise in multi-drug resistant bacteria that were not present when semi-synthetic broad spectrum spectinomycin analogs were last examined, we reinvestigated the potential for developing novel spectinomycin analogs as treatments for drug resistant organisms. In recent work we have found spectinomycin core tractable for advanced synthetic modifications producing several series of analogs that maintain the excellent ribosomal affinity of spectinomycin and access a unique binding pocket at the interface of 30S ribosome Helix 34 and a loop of ribosomal protein RpsE. These compounds have an excellent safety profile and far superior chemical stability to spectinomycin. In these efforts, we have recently discovered a novel series of aryl substituted aminospectinomycins with good antibacterial activities. The most potent of our compounds in our initial set demonstrate: good broad spectrum anti-bacterial activity including activity against
NIAID priority biodefense pathogens; on target inhibition of protein synthesis; good pharmacokinetic profiles; and excellent anti-S. pneumoniae activity in vivo. We believe the aminospectinomycins represent an important rediscovery of a neglected chemotype that can be used for the treatment of drug resistant and biodefense infections. The further development of this series will be pursued in three aims to: (i) Perform further structure based design and synthesis of novel aminospectinomycins with high antibacterial potency in seven targeted subseries; (ii) Confirm the mode of action of emerging leads and study the potential for cross resistance and inactivation; (iii) Perform lead development through five stages of detailed tests that include a full antimicrobial assessment, in vitro ADME, pharmacokinetic testing, toxicologic and in vivo efficacy experiments. After each stage, the data will be used to guide the design and synthesis of future generations of compounds and to select the best compounds to move on to the next stage such that viable, well characterized drug candidates will emerge from this study suitable for preclinical development.
描述(由申请人提供):从数字上讲,抗菌药物发现中最成功的策略是对天然产物进行合成修饰,以生产新的半合成抗生素。然而,这种方法只成功地应用于少数精选的支架。重新审视这种方法,我们重点研究了低分子量抗生素大观霉素,尽管它具有安全的药理学特征,但我们认为它被忽视了。Spectinomycin是一种氨基环醇类抗生素,通过与30S核糖体结合在一个独特的位点上特异性抑制细菌蛋白质合成,该位点在细菌病原体中高度保守。虽然大观霉素在无细胞检测中是有效的,但它的临床应用仅限于淋病奈瑟菌感染的二线治疗。在20世纪80年代,人们曾尝试开发大观霉素类似物,结果发现了trospectinomycin,该药物对不同细菌病原体的活性有所提高,并进入后期临床试验,然后因商业原因被撤回,这证实了修改该核心以获得更有效的药物的潜力。鉴于最近在半合成广谱大观霉素类似物检测时不存在的多重耐药细菌的增加,我们重新研究了开发新型大观霉素类似物作为耐药生物治疗的潜力。在最近的工作中,我们发现大霉素核心易于进行高级合成修饰,产生了几个系列的类似物,这些类似物保持了大霉素优异的核糖体亲和力,并进入30S核糖体Helix 34和核糖体蛋白RpsE环的界面上的独特结合袋。这些化合物具有良好的安全性和远优于大观霉素的化学稳定性。在这些努力中,我们最近发现了一系列新的芳基取代氨基大观菌素,具有良好的抗菌活性。最有效的化合物在我们的初始设置显示:良好的广谱抗菌活性,包括活性对
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 69.2万 - 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:
$ 69.2万 - 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:
$ 69.2万 - 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:
$ 69.2万 - 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:
$ 69.2万 - 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:
$ 69.2万 - 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:
8495235 - 财政年份:2010
- 资助金额:
$ 69.2万 - 项目类别:
相似海外基金
Aminoglycosides with reduced ototoxicity via miRNA targeting
通过 miRNA 靶向降低耳毒性的氨基糖苷类药物
- 批准号:
9891947 - 财政年份:2019
- 资助金额:
$ 69.2万 - 项目类别:
Aminoglycosides with reduced ototoxicity via miRNA targeting
通过 miRNA 靶向降低耳毒性的氨基糖苷类药物
- 批准号:
9982540 - 财政年份:2019
- 资助金额:
$ 69.2万 - 项目类别:
Antibacterial properties of amphiphilic aminoglycosides
两亲性氨基糖苷类药物的抗菌特性
- 批准号:
524825-2018 - 财政年份:2018
- 资助金额:
$ 69.2万 - 项目类别:
University Undergraduate Student Research Awards
Nanobiocapteurs de résonance des plasmons de surface pour les aminoglycosides
氨基糖苷类表面等离激元共振的纳米生物捕获剂
- 批准号:
495915-2016 - 财政年份:2016
- 资助金额:
$ 69.2万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
Designing new aminoglycosides to alleviate inner ear toxicity
设计新的氨基糖苷类药物以减轻内耳毒性
- 批准号:
8943277 - 财政年份:2015
- 资助金额:
$ 69.2万 - 项目类别: