Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes
药物耐受性、细菌异质性和不良结核病治疗结果
基本信息
- 批准号:10271651
- 负责人:
- 金额:$ 56.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-23 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdherenceAffectBacillusBiologicalBiological AssayBiological MarkersCellsCharacteristicsClinicalCodeCollectionDNADevelopmentDiseaseDrug CombinationsDrug ToleranceDrug resistanceEnvironmentEvaluationEvolutionFrameshift MutationFrequenciesGene ExpressionGenesGeneticGenetic ScreeningGenetic TranscriptionGenus MycobacteriumGrowthHeterogeneityImmuneImmunityKnock-outLaboratoriesLeadLengthLibrariesLinkMachine LearningMetabolicMicroscopyMycobacterium tuberculosisOutcomePathway AnalysisPatientsPharmaceutical PreparationsPharmacotherapyPhasePhenotypePopulationPopulation HeterogeneityPredispositionProteinsPublic HealthRegulonRelapseResistanceRoboticsRoleSystemSystems BiologyTestingTherapeuticTimeTreatment FailureTreatment outcomeTuberculosisVariantWorkcostdata integrationgene complementationgenetic predictorsgenetic resistancegenomic locusimprovedinnovationmetabolomicsmutantnetwork modelsnovelresistance mechanismresponsesuccesstooltranscription factortranscriptometranscriptome sequencingtranscriptomicstreatment durationtuberculosis chemotherapytuberculosis drugstuberculosis treatment
项目摘要
ABSTRACT - PROJECT 4
Perhaps the greatest barrier to improving tuberculosis (TB) treatment outcomes is the six months of multi-
drug therapy that is required to reliably cure a patient with active disease. Lengthy therapy is both costly and
leads to poor adherence. This project aims to understand the bacterial factors responsible for lengthy TB
treatment, TB treatment failure, and relapse. Mycobacterium tuberculosis (Mtb), the causative agent of TB has
developed an exquisite ability to adapt to its environment. Drug treatment can lead to the development of
“phenotypically drug-resistant” (i.e. drug tolerant) subpopulations that persist for long periods, as well as atypical
very-low level drug resistant mutants (i.e. elevated sub-breakpoint MIC strains) that can eventually relapse
despite months of seemingly effective drug treatment. Our overriding hypothesis is that the length of time
required to treat TB and the adverse TB outcomes that can occur even with adequate therapy are strongly linked
to phenotypic drug resistance and low-level genetic drug resistance mechanisms that can be present in Mtb
subpopulation pre-treatment, or that arise during treatment. This project will apply novel tools we have
developed, including One-cell Doubling Evaluation of Living Arrays of Mycobacterium (ODELAM), a robotic
Transwell Tolerance and Resistance (TTR) system, a complete library of transcription factor inducible (TFI)
strains, and constitutively tolerant glpK mutant Mtb strains to investigate the mechanisms that underlie these
bacterial states, as well as the heterogeneous expression of tolerance and low level resistance in different Mtb
sub-populations. Expanding from well-defined laboratory strains to a diverse collection of well characterized
clinical Mtb strains associated with either cure or relapse, we will develop a mechanistic understanding of these
still poorly characterized bacterial phenotypes and their role in treatment outcome. These discoveries will lead
to important opportunities for developing targeted TB treatments that increase therapeutic success while
shortening treatment times. This work will be conducted in three related aims: Aim 1. Define the links between
heterogeneity and phenotypic drug tolerance in Mtb. Aim 2. Determine the role of Mtb phase variation on
population heterogeneity, drug tolerance and emergent drug resistance. Aim 3. Assess role(s) of genes,
networks, and population heterogeneity in clinical isolates with defined treatment-related phenotypes.
摘要-项目4
也许改善结核病(TB)治疗结果的最大障碍是6个月的多-
可靠地治愈患有活动性疾病的患者所需的药物疗法。长期治疗既昂贵,
导致粘附性差。该项目旨在了解导致长期结核病的细菌因素
治疗、结核病治疗失败和复发。结核分枝杆菌(Mtb),结核病的病原体,
进化出了适应环境的精妙能力药物治疗可导致
长期存在的“表型耐药”(即耐药)亚群,以及非典型耐药亚群。
最终可能复发的极低水平耐药突变株(即亚折点MIC菌株升高)
尽管几个月的药物治疗看似有效。我们最重要的假设是
治疗结核病所需的药物和即使采用适当治疗也可能发生的结核病不良结局之间存在密切联系
表型耐药和低水平的遗传耐药机制,可以存在于结核分枝杆菌
治疗前或治疗期间出现的亚群。该项目将应用我们拥有的新颖工具
开发,包括单细胞倍增评估活阵列的分枝杆菌(ODELAM),机器人
Transwell耐受和抗性(TTR)系统,一个完整的转录因子诱导(TFI)文库,
菌株,和组成型耐受glpK突变Mtb菌株,以研究这些机制的基础
细菌状态,以及不同Mtb中耐受性和低水平抗性的异质性表达
亚种群。从定义明确的实验室菌株扩展到各种特征明确的
与治愈或复发相关的临床Mtb菌株,我们将对这些菌株的机制进行了解。
细菌表型和它们在治疗结果中的作用的特征仍然很差。这些发现将导致
开发靶向结核病治疗的重要机会,
缩短治疗时间。这项工作将在三个相关目标下进行:目标1。定义之间的链接
结核分枝杆菌异质性和表型耐药性目标2.确定Mtb相位变化对
群体异质性、药物耐受性和新出现的耐药性。目标3。评估基因的作用,
网络和具有确定的治疗相关表型的临床分离株的群体异质性。
项目成果
期刊论文数量(0)
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DAVID R SHERMAN其他文献
DAVID R SHERMAN的其他文献
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{{ truncateString('DAVID R SHERMAN', 18)}}的其他基金
Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes
耐药性、细菌异质性和不良结核病治疗结果
- 批准号:
10665037 - 财政年份:2021
- 资助金额:
$ 56.87万 - 项目类别:
A multifactorial pipeline to dissect combinatorial drug efficacy in Tuberculosis
剖析结核病组合药物疗效的多因素管道
- 批准号:
10117593 - 财政年份:2021
- 资助金额:
$ 56.87万 - 项目类别:
Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes
药物耐受性、细菌异质性和不良结核病治疗结果
- 批准号:
10493290 - 财政年份:2021
- 资助金额:
$ 56.87万 - 项目类别:
A multifactorial pipeline to dissect combinatorial drug efficacy in Tuberculosis
剖析结核病组合药物疗效的多因素管道
- 批准号:
10669196 - 财政年份:2021
- 资助金额:
$ 56.87万 - 项目类别:
A multifactorial pipeline to dissect combinatorial drug efficacy in Tuberculosis
剖析结核病组合药物疗效的多因素管道
- 批准号:
10465068 - 财政年份:2021
- 资助金额:
$ 56.87万 - 项目类别:
Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes
药物耐受性、细菌异质性和不良结核病治疗结果
- 批准号:
10907961 - 财政年份:2021
- 资助金额:
$ 56.87万 - 项目类别:
Parallel Microscopic Determination of Fitness (PMDF) to Assess Growth and Viability of Mycobacterium tuberculosis
平行显微适应性测定 (PMDF) 评估结核分枝杆菌的生长和活力
- 批准号:
9089849 - 财政年份:2015
- 资助金额:
$ 56.87万 - 项目类别:
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