Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens
针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂
基本信息
- 批准号:10563142
- 负责人:
- 金额:$ 79.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:Affinity ChromatographyAnimal ModelAnti-Bacterial AgentsAntibiotic TherapyAntibioticsBacteriaBindingBinding ProteinsBiological AssayCellsDaptomycinDataDefectDerivation procedureDrug KineticsDyesElectron MicroscopyEndocarditisEnsureEnterococcusEnterococcus faecalisEnterococcus faeciumEvaluation StudiesExhibitsFrequenciesGeneticGenomicsGoalsGram-Positive BacteriaHospitalsIn VitroInfectionInfection ControlInfectious Skin DiseasesInfective endocarditisLeadLength of StayLibrariesLinezolidLipid BilayersLipidsMass Spectrum AnalysisMeasuresMedicineMembraneMicrosomesMinnesotaModelingModificationMolecularMulti-Drug ResistanceMusMutationNew AgentsNosocomial InfectionsOrganismOryctolagus cuniculusPathogenicityPharmaceutical PreparationsPlasma ProteinsPositioning AttributeProceduresPropertyProteomicsPublic HealthPublishingQuinazolinesQuinolonesResearchResistanceSafetySeriesSerumSolubilitySpecificityStaphylococcus aureus infectionStaphylococcus epidermidisStreptococcus pneumoniaeStructureStructure-Activity RelationshipToxic effectUniversitiesVancomycinWorkactivity-based protein profilinganalogaqueousbactericidebiochemical toolsbiophysical toolscarbonyl groupcrosslinkcytotoxicitydesigndrug developmentdrug discoverydrug dispositionefficacy evaluationefficacy studyimprovedin vivolipophilicitymedical schoolsmethicillin resistant Staphylococcus aureusmutantnovelpathogenquinolinescaffoldscreeningsimulation
项目摘要
Abstract
Infections due to resistant Gram+ organisms are on the rise, likely due to a variety of factors including longer
hospital stay, increased frequency of invasive procedures and pervasive antibiotic therapy. Compounding
the problem is the emergence of multi-drug resistance (MDR) among many Gram+ pathogens (MRSA, S.
epidermidis, Enterococcus and S. pneumoniae). Despite antibiotic stewardship and infection control, new
agents against these Gram+ pathogens are urgently needed. After screening a ~60,000 preselected
compound library, we obtained DNAC-2, a 4-hydroxyquinoline derivative, that exhibited antibacterial activities
against MRSA and Enterococcus. We subsequently synthesized 3 series of analogues involving over 50
compounds. Two of these analogues in the 2th series, JRS-3-56 (compound 1) and JRS-4-32 (compound 2),
were cidal against MRSA, S. epidermidis, E. faecalis and E. faecium, with MIC ≤0.2 μg/ml. However, both 1
and 2 have poor predicted aqueous solubility with high cLogP (7.7 and 6.0, respectively). Conversion of
quinoline to quinazoline for 1 improved the cLogP (from 6.06 to 5.08) but led to a slight increase in MIC (0.25
to 2 µg/ml). In the latest series, we introduced a carbonyl group at C-4 and a C to N substitution at the C-1
position, yielding compounds 3 and 4 with low cLogPs and very low MIC (0.06 µg/ml for USA300),
accompanied by a much tighter SAR. Using macromolecular synthesis assays, membrane-specific dye FM4-
64 and electron microscopy studies, we have evidence that 1 and 2 target the Gram+ membrane (3 and 4
also resulted in membrane defect as detected by the FM4-64 dye), but not Gram- or eukaryotic membrane,
thus implying some degree of specificity. However, the exact target of these compounds which likely differs
from daptomycin, is not known. In this application, we seek to define the mechanism of action of these
quinoline/quinolone derivatives and further explore the SAR that governs in vitro and in vivo activities and
drug disposition properties. Accordingly, we have the following specific aims: 1) design and synthesize
quinoline/quinolone derivates by defining the SAR that governs activity against major Gram+ pathogens and
drug disposition properties (MIC, solubility, overt toxicity and serum binding etc.); 2) delineate the mechanism
of action of the quinoline/quinolone derivatives with genetic, biochemical and biophysical tools; 3)
pharmacokinetic and efficacy studies where candidates compounds will be evaluated for their drug
disposition properties to ensure safety and selectivity followed by selection of “lead” compounds for full PK
evaluation and efficacy studies with two animal models. The goal of these studies is to identify “druggable
membrane-active compounds” with broad Gram+ activity. If successful, we believe these compounds will
represent a new class of membrane-active compounds that offer a significant advance in drug development.
摘要
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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Ambrose Lin Yau Cheung其他文献
Ambrose Lin Yau Cheung的其他文献
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{{ truncateString('Ambrose Lin Yau Cheung', 18)}}的其他基金
Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens
针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂
- 批准号:
9973439 - 财政年份:2020
- 资助金额:
$ 79.94万 - 项目类别:
Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens
针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂
- 批准号:
10331864 - 财政年份:2020
- 资助金额:
$ 79.94万 - 项目类别:
Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens
针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂
- 批准号:
10117071 - 财政年份:2020
- 资助金额:
$ 79.94万 - 项目类别:
Optimization of a novel compound that enhances the activity of beta-lactams against Gram+ bacteria
增强 β-内酰胺抗革兰氏菌活性的新型化合物的优化
- 批准号:
9296686 - 财政年份:2017
- 资助金额:
$ 79.94万 - 项目类别:
Bypassing the restriction barrier to improve transformation in S. epidermidis
绕过限制性屏障以改善表皮葡萄球菌的转化
- 批准号:
9386188 - 财政年份:2017
- 资助金额:
$ 79.94万 - 项目类别:
Regulation of SsrA-mediated proteolysis of S. aureus
SsrA 介导的金黄色葡萄球菌蛋白水解的调节
- 批准号:
8951755 - 财政年份:2015
- 资助金额:
$ 79.94万 - 项目类别:
Regulation of SsrA-mediated proteolysis of S. aureus
SsrA 介导的金黄色葡萄球菌蛋白水解的调节
- 批准号:
9089861 - 财政年份:2015
- 资助金额:
$ 79.94万 - 项目类别:
The role of CshA and CshB in selective mRNA protection in S. aureus
CshA 和 CshB 在金黄色葡萄球菌选择性 mRNA 保护中的作用
- 批准号:
8665389 - 财政年份:2013
- 资助金额:
$ 79.94万 - 项目类别:
The role of CshA and CshB in selective mRNA protection in S. aureus
CshA 和 CshB 在金黄色葡萄球菌选择性 mRNA 保护中的作用
- 批准号:
8830428 - 财政年份:2013
- 资助金额:
$ 79.94万 - 项目类别:
The role of CshA and CshB in selective mRNA protection in S. aureus
CshA 和 CshB 在金黄色葡萄球菌选择性 mRNA 保护中的作用
- 批准号:
8557227 - 财政年份:2013
- 资助金额:
$ 79.94万 - 项目类别:
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