Susceptibility and resistance of multidrug-resistant gram-negative bacteria to novel beta-lactam/beta-lactamase inhibitor combinations
多重耐药革兰氏阴性菌对新型β-内酰胺/β-内酰胺酶抑制剂组合的敏感性和耐药性
基本信息
- 批准号:10748676
- 负责人:
- 金额:$ 48.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-07 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffinityAnti-Bacterial AgentsAntibioticsBacteriaBase PairingBindingBiological AssayCeftazidimeClinicalClinical ResearchClinical TrialsCollectionComplexDataDevelopmentDrug ExposureDrug resistanceEnhancersEnterobacter cloacaeEscherichia coliExhibitsExposure toExtended-spectrum β-lactamaseFiberFrequenciesFutureGene Expression ProfilingGenomicsGoalsGram-Negative BacteriaGrowthInfectionKlebsiella pneumoniaeKnowledgeLactamaseLactamsMediatingMethodsMethylationModelingMonobactamsMulti-Drug ResistanceMultiple Bacterial Drug ResistanceMusMutationOrganismPatientsPenicillin Binding Protein 2Pharmaceutical PreparationsPredispositionPseudomonas aeruginosaRegimenResearch Project GrantsResistanceResistance developmentRiskRoleSafetySerineTestingThigh structureTimeWorkantimicrobialbacterial resistancebeta-Lactamasebeta-Lactamscarbapenemaseclinical developmentgenome sequencingin vitro Assayin vivoinhibitorinhibitor therapynovelnovel therapeuticspathogenpreclinical studypreservationpreventpriority pathogenresilienceresistance frequencyresistance mechanismresponsesimulationsuicide substratestranscriptome sequencingtranscriptomicswhole genome
项目摘要
Project Summary/Abstract
Antibiotics in the b-lactam/b-lactamase inhibitor (BLBLI) class are among the mainstays of antimicrobial
treatment for gram-negative bacteria such as E. coli and Pseudomonas aeruginosa. Until recently, all b-
lactamase inhibitors in these combinations were themselves b-lactam compounds that lacked direct antimicrobial
activity. However, bacteria are increasingly developing resistance to all currently available BLBLIs. To address
this problem, new combinations are being developed that incorporate novel diazabicyclooctane (DBO) b-
lactamase inhibitors, which are non-b-lactam compounds that possess intrinsic direct antimicrobial activity
mediated by binding to penicillin-binding protein 2 (PBP2). While the expanded spectrum of these new
combinations is promising, the highly multidrug-resistant bacteria they will be used to treat are prone to the
development of additional resistance mechanisms, and PBP2-mediated antibacterial activity in particular is
known to be vulnerable to the emergence of resistance during treatment. The overall goal of this project is to
characterize the development of resistance to novel DBO-containing BLBLIs in order to discover how best to
make use of them while preventing the emergence of resistance. In Aim #1, rates of resistance to DBO-
containing BLBLIs will be assessed among a large, diverse collection of gram-negative bacterial strains including
E. coli, Klebsiella pneumoniae, Enterobacter cloacae complex, and P. aeruginosa. In Aim #2, mechanisms of
resistance to these agents will be investigated using two different ‘omics approaches. First, whole genome
sequencing will be used to identify mutations in strains in which resistance has developed. Second, gene
expression profiling using RNA-Seq will be employed to investigate the transcriptomic response of both
susceptible and resistant bacteria to DBO-containing BLBLI treatment. The goal of Aim #3 is to understand how
to prevent resistance to DBO-containing BLBLIs in models that better simulate in vivo treatment conditions. A
time-kill assay, a hollow-fiber infection model, which allows for simulation of changing antibiotic concentrations
over time, and a mouse thigh infection model will be employed to identify combinations that prevent resistance
over longer periods of drug exposure, and whole genome sequencing of resistant isolates will be used to
compare resistance-conferring mutations that occur in these models to those observed in standard in vitro
assays. The proposed project, when completed, will provide a guide to the most effective ways to utilize novel
DBO-containing BLBLIs in order to effectively treat patients with MDR infections while preventing the emergence
of resistance.
项目摘要/摘要
β-内酰胺/b-内酰胺酶抑制剂(BLBLI)类抗生素是抗菌药物的支柱之一
革兰氏阴性菌的治疗,如大肠杆菌和铜绿假单胞菌。直到最近,所有的b-
这些组合中的内酰胺酶抑制剂本身就是缺乏直接抗菌剂的β-内酰胺类化合物。
活动。然而,细菌对目前所有可用的BLBLI都产生了越来越多的抗药性。致信地址
对于这个问题,正在开发新的组合,其中包括新的二氮杂双环辛烷(DBO)b-
内酰胺酶抑制剂,是具有内在直接抗菌活性的非β-内酰胺类化合物
通过与青霉素结合蛋白2(PBP2)结合而介导。虽然这些新的扩展频谱
组合是有希望的,它们将被用来治疗的高度耐多药细菌容易
其他耐药机制的发展,特别是PBP2介导的抗菌活性
已知在治疗过程中容易出现耐药性。这个项目的总体目标是
表征对新型含DBO的BLBLIs的抗性发展,以发现如何最好地
在利用它们的同时,防止出现耐药性。在目标1中,对DBO的抵抗率-
将在一大批不同的革兰氏阴性细菌中对含有BLBLI进行评估,包括
大肠埃希菌、肺炎克雷伯氏菌、阴沟肠杆菌复合体和铜绿假单胞菌。在目标2中,机制
对这些药物的耐药性将使用两种不同的组学方法进行调查。第一,全基因组
测序将用于识别已经产生抗药性的菌株的突变。第二,基因
使用RNA-Seq的表达谱将被用来研究两者的转录反应
对含有DBO的BLBLI处理的敏感和抗药性细菌。目标3的目标是了解如何
在更好地模拟体内治疗条件的模型中防止对含有DBO的BLBLI的耐药性。一个
时间杀死试验,一种中空纤维感染模型,允许模拟变化的抗生素浓度
随着时间的推移,小鼠大腿感染模型将被用来识别防止耐药性的组合
在更长的药物暴露时间内,耐药菌株的全基因组测序将用于
将这些模型中发生的导致耐药性的突变与在体外观察到的标准突变进行比较
化验。拟议的项目完成后,将为利用小说的最有效方式提供指南
含DBO的BLBLIs在有效治疗MDR感染患者的同时防止其出现
抵抗的力量。
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)
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Thea Brennan-Krohn其他文献
Thea Brennan-Krohn的其他文献
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{{ truncateString('Thea Brennan-Krohn', 18)}}的其他基金
Identification of potentiators of antimicrobial activity against multidrug-resistant Burkholderia cepacia complex infections in cystic fibrosis
囊性纤维化中多重耐药洋葱伯克霍尔德杆菌复合感染抗菌活性增强剂的鉴定
- 批准号:
10358653 - 财政年份:2021
- 资助金额:
$ 48.44万 - 项目类别:
Antimicrobial Synergy for Carbapenem-Resistant Enterobacteriaceae
对碳青霉烯类耐药肠杆菌科细菌的抗菌协同作用
- 批准号:
10328479 - 财政年份:2018
- 资助金额:
$ 48.44万 - 项目类别:
Antimicrobial Synergy for Carbapenem-Resistant Enterobacteriaceae
对碳青霉烯类耐药肠杆菌科细菌的抗菌协同作用
- 批准号:
10084800 - 财政年份:2018
- 资助金额:
$ 48.44万 - 项目类别:
Antimicrobial Synergy for Carbapenem-Resistant Enterobacteriaceae - Administrative Supplement
耐碳青霉烯类肠杆菌科细菌的抗菌协同作用 - 行政补充
- 批准号:
10117330 - 财政年份:2018
- 资助金额:
$ 48.44万 - 项目类别:
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