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/文摘
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
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:
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