Drugs targeting persistent Mycobacterium Tuberculosis
针对持续性结核分枝杆菌的药物
基本信息
- 批准号:8439505
- 负责人:
- 金额:$ 68.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2017-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdverse effectsAffinityAntibioticsAntitubercular AgentsBacterial InfectionsBindingBiologicalCarbamatesCellsChemistryChronicDiseaseDrug KineticsDrug Resistant TuberculosisDrug TargetingDrug resistanceDrug resistance in tuberculosisDrug-sensitiveEvolutionExtreme drug resistant tuberculosisFundingFutureGene MutationGenetic ScreeningGrowthHumanitiesIn VitroInfectionLaboratoriesLeadMediatingMicrobial BiofilmsMicrobial GeneticsModelingMulti-Drug ResistanceMusMycobacterium smegmatisMycobacterium tuberculosisMycobacterium tuberculosis H37RvPatientsPharmaceutical PreparationsPhenotypeProteinsProteomicsResearchResistanceRifampinSterilizationStructure-Activity RelationshipThiophenesTimeTuberculosisWorkanalogbactericidebasebenzothiazoleburden of illnesschemotherapydrug developmentgenome sequencingglobal healthhigh throughput screeninghuman diseaseimprovedin vitro Modelin vitro activityin vivoin vivo Modelinhibitor/antagonistisoniazidkillingsmouse modelmutantnovelnovel therapeuticsphysical propertypublic health relevanceresearch studyresistance alleleresistant strainsmall moleculetreatment durationtuberculosis drugstuberculosis treatment
项目摘要
DESCRIPTION (provided by applicant): Tuberculosis (TB) is a devastating bacterial disease for two reasons: First because there are huge numbers involved, approximately 1/3 of humanity is infected, about fifteen million people are in active disease at any one time and about two million die of TB each year. Secondly, TB is one of the most difficult bacterial infections to trea. To treat fully drug-sensitive cases of active TB takes six months and requires four different antibiotics. Multi-Drug Resistant (MDR) and eXtensively Drug Resistant (XDR) TB are resistant to some, or all, respectively, of the first line antibiotics and require drugs that are more dangerous to the patient, often must be given intravenously, and are much more expensive. There is an urgent need for faster-acting antibiotics against TB with fewer side effects and for antibiotics that are effective against MDR and XDR TB. We found that mutants unable to make biofilms are more sensitive to antibiotic in vitro during planktonic growth. Inspired by these results, we hypothesized that in vitro biofilm formation could be a unique phenotype to develop a high-throughput screen for inhibitors with novel mechanism(s) of action. A cell-based screen of 70,000 compounds for molecules that inhibit biofilm formation in Mycobacterium smegmatis yielded a number of compounds that strongly inhibit biofilm formation in Mycobacterium tuberculosis (Mtb). One candidate TCA1 has bactericidal activity against both drug susceptible and drug resistant Mtb and synergizes with rifampcin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition TCA1 showed bactericidal activity against both replicating and non-replicating Mtb in vitro. Furthermore, we have demonstrated that TCA1 is active in a Mtb mouse infection model both independently and in conjunction with INH or RIF suggesting that it is a promising lead for drug development. We propose to characterize the biological mechanism of TCA1 and carry out structure-activity relationship (SAR) studies to improve the potency and pharmacokinetics of this molecule against susceptible and drug resistant Mtb. The result will be robust lead candidates with in vivo proof of efficacy that can be further optimized and developed through future funded collaborative efforts as novel therapeutics for the treatment of TB.
描述(由申请人提供):结核病(TB)是一种毁灭性的细菌疾病,有两个原因:首先是因为涉及大量数量,大约1/3的人类感染了人类,大约有1500万人在任何时候都患有活性疾病,每年大约有200万人死亡。其次,结核病是最困难的细菌感染之一。为了治疗全药物敏感的病例,活性结核病需要六个月,需要四种不同的抗生素。多药耐药(MDR)和广泛的耐药性(XDR)结核病分别对第一线抗生素的某些或全部抗性,并且需要对患者更危险的药物,通常必须静脉注射,并且昂贵得多。迫切需要对TB进行更快的抗生素,具有更少的副作用以及对MDR和XDR TB有效的抗生素。我们发现,在浮游生长过程中,无法制作生物膜的突变体对体外的抗生素更敏感。受这些结果的启发,我们假设体外生物膜的形成可能是一种独特的表型,可以为具有新型作用机制的抑制剂开发高通量屏幕。基于细胞的70,000种化合物的分子,可抑制分枝杆菌中生物膜形成的分子,产生了多种化合物,这些化合物强烈抑制结核分枝杆菌(MTB)中的生物膜形成。一位候选TCA1具有对药物易感和耐药性MTB的杀菌活性,并与Rifampcin(RIF)或Isoniaiazid(INH)协同体外灭菌。另外,TCA1在体外表现出针对复制和非复制MTB的杀菌活性。此外,我们已经证明了TCA1在MTB小鼠感染模型中具有活性,并与INH或RIF结合使用,这表明这是药物发育的有希望的铅。我们建议表征TCA1的生物学机制并进行结构活性关系(SAR)研究,以提高该分子对易感和耐药MTB的效力和药代动力学。结果将是强大的主要候选人,并具有在体内的效力证明,可以通过将来的资助协作努力作为TB治疗的新型治疗方法进行进一步优化和开发。
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(1)
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WILLIAM Robert JACOBS其他文献
WILLIAM Robert JACOBS的其他文献
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针对持续性结核分枝杆菌的药物
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$ 68.99万 - 项目类别:
Drugs targeting persistent Mycobacterium Tuberculosis
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