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
基本信息
- 批准号:10358653
- 负责人:
- 金额:$ 21.88万
- 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:2021-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAlbuminsAmericanAmino AcidsAnaerobic BacteriaAnimal ModelAnti-Bacterial AgentsAntibiotic ResistanceAntibiotic TherapyAntibioticsAntidepressive AgentsAntimicrobial susceptibilityAvidityBacteriaBiological AssayBurkholderia cepacia complexCeftazidimeCharacteristicsChloride ChannelsClinicalCollectionCystic FibrosisDNADevelopmentDiseaseDoseDrug resistanceEnvironmentEvaluationExposure toFDA approvedFrightFutureGastrointestinal tract structureGenetic DiseasesGoalsGram-Negative BacteriaGrowthHospitalizationHumanIn VitroIndividualInfectionInhalationInvestigationIronLevaquinLifeLongevityLungLung infectionsMeropenemMicrobial BiofilmsMinocyclineMucinsMucous body substanceMulti-Drug ResistanceNebulizerOrganismOxygenPatientsPersonsPharmaceutical ChemistryPharmaceutical PreparationsPropertyPulmonary Cystic FibrosisQuality of lifeRegimenResearchResearch Project GrantsResistanceRespiratory SystemSelective Serotonin Reuptake InhibitorSertralineSpeedSputumTechniquesTestingTherapeuticTimeTobramycinTrimethoprim-SulfamethoxazoleUnited StatesViscosityWorkalternative treatmentantimicrobialbench to bedsideclinical practicecystic fibrosis infectioncystic fibrosis patientsdesigneffective therapyemerging antibiotic resistancehigh throughput screeningimprovedin vitro Modelin vitro activitylung colonizationmortalitymulti-drug resistant pathogennovelnovel therapeuticspathogenpressurepreventresistance mechanismresistant strainresponsescaffoldsmall moleculesynergismsystemic toxicitytreatment strategy
项目摘要
Project Summary/Abstract
Pulmonary exacerbations are one of the most common manifestations of cystic fibrosis (CF), a life-limiting,
multisystem disease that affects 30,000 Americans. These exacerbations are often caused by highly drug-
resistant Gram-negative bacteria that colonize the lungs of people with CF. Among such organisms, the most
feared is the Burkholderia cepacia complex (Bcc). Bcc have extensive intrinsic antibiotic resistance and readily
acquire further resistance mechanisms under selective pressure during antibiotic treatment; pan-resistant strains
can emerge following repeated antibiotic courses. Bcc infection is associated with frequent hospitalizations and
increased mortality in people with CF, but there are no new antibiotics with activity against BCC in the
development pipeline, and alternative treatment strategies are urgently needed. The goal of the proposed
research is to identify known bioactive compounds that have activity against Bcc either alone or in combination
with antibiotics. This work will be carried out through two aims. In Aim 1, we will test 14,000 known bioactive
small molecules, including all FDA-approved drugs, both alone and in combination with six antibiotics commonly
used to treat Bcc (meropenem, ceftazidime, minocycline, levofloxacin, trimethoprim-sulfamethoxazole, and
tobramycin, each at an individually ineffective concentration), to identify compounds and compound/antibacterial
combinations that inhibit growth of a representative Bcc isolate. In Aim 2, we will further characterize the activity
of promising compounds identified in the screen using several complementary in vitro models. First, we will
perform spectrum-of-activity and dose-response testing of compounds and combinations against a collection of
30 Bcc isolates using inkjet printer-assisted checkerboard array synergy studies as well as time-kill synergy
studies. We will also evaluate the capacity of compounds to prevent the emergence of antibiotic resistance during
treatment. Then, in order to better approximate the environment in which bacteria live in the lungs of people with
CF, which is characterized by increased viscosity, high concentrations of mucin, albumin, amino acids, and free
DNA, and lower oxygen tension relative to standard in vitro antimicrobial susceptibility testing conditions, we will
test compounds and combinations using an artificial sputum medium in a microaerophilic environment. With this
approach, we will assess whether activity is maintained under conditions more closely resembling those in which
they would be used in clinical practice. When the project is completed, we expect to have identified a collection
of molecules with previously unrecognized activity against Bcc and to have determined which of these are most
likely to be clinically effective in people with CF. Identification of well-characterized compounds that have
potential therapeutic activity against Bcc will facilitate future evaluation in animal models and human trials in
order to develop desperately needed new therapeutic options for Bcc.
项目总结/摘要
肺恶化是囊性纤维化(CF)最常见的表现之一,
影响了3万美国人的多系统疾病这些恶化通常是由高药物引起的-
耐药革兰氏阴性菌,定植于CF患者的肺部。在这些生物中,
洋葱伯克霍尔德氏菌复合体(Burkholderia cepacia complex,BCC)BCC具有广泛的内在抗生素耐药性,
在抗生素治疗期间的选择压力下获得进一步的耐药机制;泛耐药菌株
可以在反复使用抗生素后出现。BCC感染与频繁住院有关,
CF患者的死亡率增加,但目前还没有新的抗生素对BCC具有活性,
发展管道和替代治疗战略是迫切需要的。建议的目标
研究是鉴定已知的单独或组合具有抗BCC活性的生物活性化合物
抗生素。这项工作将通过两个目标进行。在目标1中,我们将测试14,000种已知的生物活性物质,
小分子,包括所有FDA批准的药物,无论是单独使用还是与六种抗生素联合使用,
用于治疗基底细胞癌(美罗培南、头孢他啶、米诺环素、左氧氟沙星、甲氧苄啶-磺胺甲恶唑,
妥布霉素,各自处于单独的无效浓度),以鉴定化合物和化合物/抗菌剂
抑制代表性BCC分离物生长的组合。在目标2中,我们将进一步描述
在使用几种互补的体外模型筛选中鉴定出的有前途的化合物。一是
对化合物和组合进行活性谱和剂量反应测试,
使用喷墨打印机辅助棋盘阵列协同研究以及时间杀灭协同研究的30个BCC分离株
问题研究我们还将评估化合物在治疗期间防止抗生素耐药性出现的能力。
治疗然后,为了更好地近似细菌在患有肺结核的人的肺中生活的环境,
CF,其特征在于粘度增加,粘蛋白、白蛋白、氨基酸和游离氨基酸浓度高,
DNA,以及相对于标准体外抗菌药物敏感性测试条件的较低氧分压,我们将
在微需氧环境中使用人工痰培养基测定测试化合物和组合。与此
我们将评估是否在更接近于以下情况的条件下保持活动:
它们将用于临床实践。当项目完成后,我们希望已经确定了一个集合,
的分子与以前未认识到的活性对BCC,并已确定其中哪些是最重要的
可能对CF患者具有临床有效性。鉴定具有以下特征的充分表征的化合物:
对BCC的潜在治疗活性将有助于未来在动物模型和人体试验中的评估,
为了开发迫切需要的新的治疗选择BCC。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Thea Brennan-Krohn其他文献
Thea Brennan-Krohn的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Thea Brennan-Krohn', 18)}}的其他基金
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
- 批准号:
10748676 - 财政年份:2023
- 资助金额:
$ 21.88万 - 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:
$ 21.88万 - 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:
$ 21.88万 - 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:
$ 21.88万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 21.88万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 21.88万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 21.88万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 21.88万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 21.88万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 21.88万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 21.88万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 21.88万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 21.88万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 21.88万 - 项目类别:
Grant-in-Aid for Early-Career Scientists