Development of an Oral Carbapenem Drug for Treatment of Drug Resistant TB
开发治疗耐药结核病的口服碳青霉烯类药物
基本信息
- 批准号:8800545
- 负责人:
- 金额:$ 21.74万
- 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:2014-03-01 至 2016-02-29
- 项目状态:已结题
- 来源:
- 关键词:AmericasAnabolismAnti-Bacterial AgentsAntibiotic ResistanceAntibioticsArea Under CurveBacteriaBacterial InfectionsBindingBioavailableBiochemicalBiological AvailabilityCarbapenemsChemicalsClavulanateClinicalCommunicable DiseasesDataDefectDevelopmentDiseaseDrug KineticsDrug TargetingDrug resistanceDrug resistance in tuberculosisDrug-sensitiveEnzymesEpidemicEvolutionFDA approvedFutureGoalsGrowthHalf-LifeHealthHumanIn VitroInfectionKnowledgeLabelLactamaseLactamsLeadManuscriptsMicrobial Antibiotic ResistanceMolecularMycobacterium tuberculosisOralPeptidoglycanPeptidyltransferasePharmaceutical ChemistryPharmaceutical PreparationsPharmacodynamicsPhasePhenotypePhysiciansPrincipal InvestigatorProdrugsPropertyPublishingRecording of previous eventsReportingResistanceRoentgen RaysScientistSocietiesStagingStructureSuperbugTestingTherapeuticTimeUnited StatesVariantadductantimicrobialbasebiophysical techniquescheminformaticscombatdesigndrug candidatedrug developmentdrug resistant bacteriaenzyme pathwayin vitro activityin vivoinhibitor/antagonistinnovationkillingsmouse modelnovelpathogenresearch studyresistant strainscaffoldtranspeptidation
项目摘要
DESCRIPTION (provided by applicant): In 2008, leading infectious diseases physician scientists representing Infectious Diseases Society of America published a report titled "The Epidemic of Antibiotic-Resistant Infection" in which they declared "We are in the midst of an emerging crisis of antibiotic resistance for microbial pathogens in the United States and throughout the world." It is widely accepted that the only means to effectively combat the widespread evolution of bacterial pathogens to resist existing drugs is to innovate new drugs that inhibit novel targets. The peptidoglycan (PG) layer is considered the Achilles' Heel of bacteria and the drugs that inhibit the final step of its synthesis, namely the ¿-lactams, represen ~60% of all antibiotics in clinical use and therefore have the highest impact in treating bacterial
infections in humans. The final step of the PG biosynthesis is catalyzed by 3,3- and 4,3-transeptidases. The ¿-lactams act by inhibiting 4,3-transpeptidases. However, there are no known agents that specifically inhibit 3,3-transpeptidases. We have shown that 3,3-transpeptidases are essential for M. tuberculosis to grow and cause disease and therefore comprise novel target for drug development. Can inhibiting this novel target usher us, once again, to a new era of effective antibacterial drugs? In this proposal we present the rationale, preliminary data, demonstrate that 3,3-transpeptidase is a novel target with the promise of a high-impact in treatment of bacterial infections and propose studies to achieve these goals. We and others have recently shown that carbapenems, a class of ¿-lactam drugs, binds and inhibits 3,3-transpeptidases. In this proposal we will test the hypothesis that variants based on the carbapenem structure can inhibit 3,3-transpeptidase activity and consequently kill M. tuberculosis. By focusing on 3,3- transpeptidase activity, an unexploited but validated drug target, we expect to develop new carbapenems that have activity against drug sensitive and resistant strains of M. tuberculosis.
描述(申请人提供):2008年,代表美国传染病学会的著名传染病内科科学家发表了一份题为《抗生素耐药感染的流行》的报告,他们在报告中宣称,我们正处于美国和世界各地微生物病原体的抗生素耐药性危机之中。人们普遍认为,有效对抗细菌病原体的广泛进化以对抗现有药物的唯一手段是创新抑制新靶点的新药。肽聚糖(PG)层被认为是细菌的阿喀琉斯之跟,是抑制细菌合成最后一步的药物,即内酰胺类药物,占临床使用的所有抗生素的60%左右,因此在治疗细菌方面效果最好
对人类的感染。PG生物合成的最后一步是由3,3-和4,3-转隔酶催化的。内酰胺类药物通过抑制4,3-转肽酶起作用。然而,目前还没有已知的药物专门抑制3,3-转肽酶。我们已经证明,3,3-转肽酶对结核分枝杆菌的生长和致病是必不可少的,因此成为药物开发的新靶点。抑制这一新靶点能否再次将我们带入有效抗菌药物的新时代?在这项提案中,我们介绍了基本原理、初步数据,证明了3,3-转肽酶是一个新的靶点,有望在细菌感染的治疗中产生高影响,并提出实现这些目标的研究。我们和其他人最近已经证明,碳青霉烯类药物是一类内酰胺类药物,可以结合和抑制3,3-转肽酶。在这项提案中,我们将测试基于碳青霉烯结构的变体可以抑制3,3-转肽酶活性从而杀死结核分枝杆菌的假设。通过专注于3,3-转肽酶活性,一个未开发但有效的药物靶标,我们希望开发出新的碳青霉烯类药物,对药物敏感和耐药的结核分枝杆菌菌株具有活性。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Non-classical transpeptidases yield insight into new antibacterials.
- DOI:10.1038/nchembio.2237
- 发表时间:2017-01
- 期刊:
- 影响因子:14.8
- 作者:Kumar P;Kaushik A;Lloyd EP;Li SG;Mattoo R;Ammerman NC;Bell DT;Perryman AL;Zandi TA;Ekins S;Ginell SL;Townsend CA;Freundlich JS;Lamichhane G
- 通讯作者:Lamichhane G
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Gyanu Lamichhane其他文献
Gyanu Lamichhane的其他文献
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{{ truncateString('Gyanu Lamichhane', 18)}}的其他基金
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- 批准号:
10264104 - 财政年份:2020
- 资助金额:
$ 21.74万 - 项目类别:
A strategy for new regimens to treat pulmonary Mycobacteroides abscessus infection
治疗肺部脓肿分枝杆菌感染的新方案策略
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10683091 - 财政年份:2020
- 资助金额:
$ 21.74万 - 项目类别:
Oral dual β-lactams to treat pulmonary M. abscessus disease
口服双β-内酰胺治疗肺脓肿分枝杆菌病
- 批准号:
10206006 - 财政年份:2020
- 资助金额:
$ 21.74万 - 项目类别:
Oral dual β-lactams to treat pulmonary M. abscessus disease
口服双β-内酰胺治疗肺脓肿分枝杆菌病
- 批准号:
10027940 - 财政年份:2020
- 资助金额:
$ 21.74万 - 项目类别:
A strategy for new regimens to treat pulmonary Mycobacteroides abscessus infection
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- 批准号:
10458704 - 财政年份:2020
- 资助金额:
$ 21.74万 - 项目类别:
A strategy for new regimens to treat pulmonary Mycobacteroides abscessus infection
治疗肺部脓肿分枝杆菌感染的新方案策略
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10096918 - 财政年份:2020
- 资助金额:
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Towards a new regimen to treat mycobacterial infection in cystic fibrosis patients
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开发治疗耐药结核病的口服碳青霉烯类药物
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- 资助金额:
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