Examining fluoroquinolone-induced DNA damage in persisters and its contributions to antibiotic resistance.
检查氟喹诺酮引起的 DNA 损伤及其对抗生素耐药性的影响。
基本信息
- 批准号:9751637
- 负责人:
- 金额:$ 39.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:Antibiotic ResistanceAntibiotic TherapyAntibioticsBacteriaCellsChemicalsChronicDNA DamageDNA Double Strand BreakDNA RepairDataDecision TreesDropsEscherichia coliEssential GenesExcisionFilamentFilmFluorescence MicroscopyFluoroquinolonesFrequenciesGeneticGenomeGrowthHealthHospitalsImmuneImmunityIncidenceIndividualInfectionInjuryKnowledgeLinkLocationMethodsMicrobial BiofilmsMicroscopyModelingMutagenesisMutationNormal CellOutcomePhasePhenotypePhysiologyPopulationPopulation ResearchProcessRampRecoveryRecurrenceRelapseReporterResearchResistanceResistance developmentRoleSOS ResponseSon of Sevenless ProteinsStatistical Data InterpretationStatistical MethodsStressSurvivorsTechniquesTestingTherapeutic InterventionTimeTreesWorkantibiotic toleranceemerging antibiotic resistanceexperienceexperimental studyfluoroquinolone resistancegenome sequencinggenome-wideinhibitor/antagonistmutantnext generation sequencingpersistent bacteriapreventresistance mutationresponsetime usewhole genome
项目摘要
Summary
Infections that contain biofilms are exceptionally difficult to treat. These infections often respond to antibiotic
therapy but quickly relapse, resulting in chronic and recurrent infections. The recalcitrance of biofilm infections
is thought to arise from the presence of bacterial persisters. Persisters are antibiotic-tolerant cells that are
genetically identical to the overall population that succumbs to antibiotics, but occupy a favorable phenotypic
niche at the time of treatment. In general, these survivors are thought to be in a state of dormancy, where the
activities of antibiotic primary targets are reduced and the extent of antibiotic-induced damage is severely
limited. The current model of a biofilm infection cycle includes clearance of normal cells by antibiotics and
immunity, both within the film and shed from it, and clearance of persisters that are shed from the film by
immunity. Immune cells are hindered from accessing persisters within the biofilm, and when the antibiotic
levels drop, persisters proceed to repopulate the film, causing a relapse infection. With every relapse, the
chance for an antibiotic-resistant mutation to occur increases, and since persisters are thought to suffer little to
no injury from antibiotic treatment, the rate at which resistant mutants should arise from persister-spawned
cultures has been assumed to be the same as that of normal bacterial populations. Recently, we discovered
that persisters to fluoroquinolones (FQ) in growth-inhibited populations experience FQ-induced DNA damage
that is equivalent to damage in bacteria that die from treatment. These unexpected results suggested that
those persisters might be mutagenized by FQ and that populations grown up from persisters, such as those of
relapse infections, would be genetically diverse and produce antibiotic-resistant mutants at high rates, which
we found to be true. These data suggest that there is a highway between persistence and antibiotic resistance
whose entrance ramp is treatment with a commonly prescribed class of antibiotics, FQs. We hypothesize that
increased understanding of FQ damage in persisters and how they survive that damage will illuminate
strategies to reduce relapse infections and hinder antibiotic resistance development. To test our hypothesis,
we will tailor a method that quantifies DNA double-strand breaks (DSBs) at the genome-scale to FQ-induced
DSBs and employ it to study strains with different persister levels; use time-lapse microscopy to interrogate the
roles of the SOS response, DNA repair, elongation, and septation to the recovery of persisters following FQ
treatment; and use genetic mutants, lineage tracking, and whole-genome sequencing to determine whether
FQ-induced mutagenesis contributes to heightened antibiotic resistance in populations derived from FQ
persisters. Collectively, these experiments and the statistical methods we will use to analyze the resulting data
will provide mechanistic knowledge of FQ persisters and how they enhance the incidence of antibiotic
resistance, which could illuminate new avenues of therapeutic intervention for recalcitrant infections.
总结
含有生物膜的感染是非常难以治疗的。这些感染通常对抗生素有反应
治疗,但很快复发,导致慢性和复发性感染。生物膜感染的预防
被认为是由细菌持续存在引起的。Persisters是一种耐缺氧细胞,
在遗传上与屈服于抗生素的总体群体相同,但占据有利的表型
在治疗的时候。一般来说,这些幸存者被认为处于休眠状态,
抗生素主要靶点的活性降低,抗生素引起的损害程度严重
有限公司目前的生物膜感染周期模型包括通过抗生素清除正常细胞,
免疫力,无论是在膜内,并从它脱落,和清除的坚持者是从膜脱落,
免疫力免疫细胞被阻止进入生物膜内的持久性,当抗生素
水平下降,坚持者继续重新填充膜,导致复发感染。每次复发,
耐药性突变发生的机会增加,而且由于坚持者被认为几乎不会受到影响,
没有抗生素治疗的伤害,耐药突变体应该从坚持产生的速度,
已经假定培养物与正常细菌群体的培养物相同。最近,我们发现
在生长抑制人群中,氟喹诺酮类药物(FQ)的持续使用者经历了氟喹诺酮类药物诱导的DNA损伤,
这相当于治疗过程中死亡的细菌的损伤。这些意想不到的结果表明,
这些坚持者可能被FQ诱变,并且从坚持者生长的种群,例如
复发感染,将是遗传多样性和产生抗药性突变体的高比率,
我们发现是真的。这些数据表明,在持久性和抗生素耐药性之间存在一条高速公路
他们的入口是用一种常用的抗生素治疗,即FQs。我们假设
增加对FQ在坚持者中的损害的理解,以及他们如何在这种损害中生存,
减少复发感染和阻止抗生素耐药性发展的战略。为了验证我们的假设,
我们将量身定制一种在基因组规模上量化DNA双链断裂(DSB)的方法,以适应荧光定量诱导的情况
DSBs,并利用它来研究具有不同持久力水平的菌株;使用延时显微镜来询问
SOS反应、DNA修复、延伸和分隔对FQ后持留菌恢复的作用
治疗;并使用遗传突变体,谱系跟踪和全基因组测序来确定是否
PQ诱导的突变有助于提高FQ来源群体的抗生素耐药性
顽固分子总的来说,这些实验和统计方法,我们将用来分析所得数据
将提供FQ持续者的机制知识,以及它们如何增加抗生素的发生率
耐药性,这可能会照亮新的途径,治疗干预的寄生虫感染。
项目成果
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Mark P Brynildsen其他文献
Mark P Brynildsen的其他文献
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{{ truncateString('Mark P Brynildsen', 18)}}的其他基金
Examining fluoroquinolone-induced DNA damage in persisters and its contributions to antibiotic resistance.
检查氟喹诺酮引起的 DNA 损伤及其对抗生素耐药性的影响。
- 批准号:
10215254 - 财政年份:2017
- 资助金额:
$ 39.98万 - 项目类别:
Exploring Persister Antibiotic Responses as a Source of Biomarkers and Elimination Strategies
探索持久性抗生素反应作为生物标志物和消除策略的来源
- 批准号:
8969012 - 财政年份:2015
- 资助金额:
$ 39.98万 - 项目类别:
Exploring Persister Antibiotic Responses as a Source of Biomarkers and Elimination Strategies
探索持久性抗生素反应作为生物标志物和消除策略的来源
- 批准号:
9066085 - 财政年份:2015
- 资助金额:
$ 39.98万 - 项目类别:
Aminoglycoside-Enabled Elucidation of Persister Metabolism
氨基糖苷类药物对持续代谢的阐明
- 批准号:
8486859 - 财政年份:2013
- 资助金额:
$ 39.98万 - 项目类别:
Aminoglycoside-Enabled Elucidation of Persister Metabolism
氨基糖苷类药物对持续代谢的阐明
- 批准号:
8605521 - 财政年份:2013
- 资助金额:
$ 39.98万 - 项目类别:
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