Characterization of MsbA inhibitors as potential antibiotic leads to treat carbapenem-resistant Enterobacteriaceae (CRE)
MsbA 抑制剂作为潜在抗生素的特性可用于治疗耐碳青霉烯类肠杆菌 (CRE)
基本信息
- 批准号:9978345
- 负责人:
- 金额:$ 24.5万
- 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:2020-08-19 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseATP-Binding Cassette TransportersAddressAmericanAminoglycosidesAnti-Bacterial AgentsAntibioticsBacterial Drug ResistanceBacterial InfectionsBinding SitesBiochemicalBiogenesisBiological AssayCDC2 geneCarbapenemsCell SurvivalCellsCellular StructuresCenters for Disease Control and Prevention (U.S.)CephalosporinsChemicalsClinicalCoculture TechniquesColistinCollaborationsCommunicable DiseasesCommunitiesComplexCryoelectron MicroscopyCrystallizationDataDeacetylaseDevelopmentDoseDrug DesignEnterobacterEnterobacteriaceaeEnterobacteriaceae InfectionsEnzymesEscherichia coliEscherichia coli drug resistanceEuropeanFosfomycinFoundationsFrightFutureGenomic Centers for Infectious DiseasesGoalsGram-Negative BacteriaHealth Care CostsHepG2HospitalsIn VitroKlebsiella pneumoniaeLactamaseLactamsLeadLeftLength of StayLettersLifeLigand BindingLipopolysaccharide Biosynthesis PathwayLipopolysaccharidesMediatingMembraneMeropenemMicrobiologyMolecular ConformationMulti-Drug ResistanceMutationNew AgentsOralOrganismPathway interactionsPatternPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPolymyxinsProteinsReportingResistanceResolutionRiskRoentgen RaysSeriesSiderophoresSolidStructureStructure-Activity RelationshipSuperbugTetracyclinesTherapeuticTimeZincantimicrobialbactericidebasebeta-Lactam Resistancecarbapenem resistancecarbapenem-resistant Enterobacteriaceaeclinically relevantcommensal bacteriadoripenemgenome sequencinggut microbiotaimprovedin vitro activityinhibitor/antagonistinnovationlead optimizationmembrane biogenesismolecular sitemortalitymutantnovelnovel therapeuticsoverexpressionpathogenperiplasmresistance frequencysmall molecule inhibitorstructural genomicstigecyclinewhole genome
项目摘要
In 2013, the CDC designated carbapenem-resistant Enterobacteriaceae (CRE) an Urgent Threat, and in 2017,
the WHO designated it a Priority 1 “critical superbug”. As few therapies remain to treat CRE, the risk of “pan-
resistant” CRE untreatable by any currently available antibiotic also exists. Entirely new agents with novel
mechanisms of action (MOA) not cross-resistant to SOC agents languish. Development of such a ‘first-in-class’
agent also offers the potential for much-needed orally-administered CRE therapeutic, thus providing a new
step-down therapy to reduce hospital stay and growing healthcare costs. Our proposal aims to develop an
entirely novel therapeutic to treat life-threatening bacterial infections due to multidrug resistant (MDR)
Enterobacteriaceae, including CRE. Using an innovative overexpression-based co-culture screen in
Escherichia coli (Ec), we identified four structurally distinct series of small molecule inhibitors targeting MsbA,
an essential and broadly conserved Gram-negative (GN) ABC transporter responsible for lipopolysaccharide
(LPS) biogenesis and construction of the Gram-negative outer membrane (OM). Building upon a solid
foundation of preliminary data, our Aims are:
Aim (A) 1. Expanded MOA studies. Aim 1 studies will expand upon our preliminary MOA and microbiological
characterization of the MsbA inhibitor (MsbAi) hits to include other GN bacteria, particularly Klebsiella
pneumoniae (Kp). Specifically, we will demonstrate Kp MsbA target inhibition in (1) an in vitro biochemical assay
and (2) a whole-cell context by determining MICs of our MsbAis against a Kp tolC strain and subsequently
selecting for MsbAisR mutants in this Kp background.
Aim 2. Demonstrate chemical tractability of MsbAis. The goal of Aim 2 is to perform Hit to Lead (H2L)
medicinal chemistry structure activity relationship (SAR) studies for each MsbAi and demonstrate >1 series is
chemically tractable and that quantifiable pre-lead optimization criteria can be established, including i) Ec and
Kp MsbA in vitro potency (IC50 < 0.25 µg/ml), ii) Ec and Kp WT activity (<16 µg/ml), and iii) > 90% HepG2 cell
viability at 50X MIC against EcΔtolC. MsbAis achieving these milestones serve as a justifiable starting point for
a future Lead Optimization leveraging the resulting SAR gained in Aim 2 and SBDD information from Aim 3.
Aim 3. Obtain Ec and Kp MsbAi-MsbA co-crystal structures in collaboration with SSGCID. The goal of
Aim 3 activities is to initiate a collaboration between Prokaryotics, Genentech, and the Seattle Structural
Genomics Center for Infectious Disease (SSGCID) led by Dr. Peter Myler to optimize conditions suitable for
obtaining high resolution x-ray crystal structures of Kp MsbA in the apo form as well as Ec and/or Kp MsbA
proteins in complex with MsbAis.
2013年,CDC将碳青霉烯抗性肠杆菌科(CRE)列为紧急威胁,2017年,
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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Terry Roemer其他文献
Terry Roemer的其他文献
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{{ truncateString('Terry Roemer', 18)}}的其他基金
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Development of a mechanistically novel Gram-negative antibiotic targeting MsbA-mediated Lipopolysaccharide Biogenesis
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10584170 - 财政年份:2022
- 资助金额:
$ 24.5万 - 项目类别:
Characterization of MsbA inhibitors as potential antibiotic leads to treat carbapenem-resistant Enterobacteriaceae (CRE)
MsbA 抑制剂作为潜在抗生素的特性可用于治疗耐碳青霉烯类肠杆菌 (CRE)
- 批准号:
10242174 - 财政年份:2020
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$ 24.5万 - 项目类别:
Development of WecA-targeting immune potentiators to treat carbapenem-resistant Enterobacteriaceae (CRE) infections
开发 WecA 靶向免疫增强剂来治疗碳青霉烯类耐药肠杆菌 (CRE) 感染
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Development of WecA-targeting immune potentiators to treat carbapenem-resistant Enterobacteriaceae (CRE) infections
开发 WecA 靶向免疫增强剂来治疗碳青霉烯类耐药肠杆菌 (CRE) 感染
- 批准号:
10470327 - 财政年份:2019
- 资助金额:
$ 24.5万 - 项目类别:
Development of a novel agent to treat antimicrobial resistant Neisseria gonorrhoeae
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9620389 - 财政年份:2018
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$ 24.5万 - 项目类别:
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- 批准号:
9814432 - 财政年份:2018
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$ 24.5万 - 项目类别:
Development of a PO-administered beta-lactam-tarocin combination agent to treat methicillin susceptible and methicillin resistant Staphylococci
开发用于治疗甲氧西林敏感和甲氧西林耐药葡萄球菌的 PO 给药 β-内酰胺-塔罗辛组合药物
- 批准号:
10662488 - 财政年份:2018
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$ 24.5万 - 项目类别:
Development of a PO-administered beta-lactam-tarocin combination agent to treat methicillin susceptible and methicillin resistant Staphylococci
开发用于治疗甲氧西林敏感和甲氧西林耐药葡萄球菌的 PO 给药 β-内酰胺-塔罗辛组合药物
- 批准号:
10547079 - 财政年份:2018
- 资助金额:
$ 24.5万 - 项目类别:
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