Disrupting Dogma: Investigating LPS Biosynthesis Inhibition as an Alternative Mechanism of Action of Aminoglycoside Antibiotics
Disrupting Dogma: Investigating LPS Biosynthesis Inhibition as an Alternative Mechanism of Action of Aminoglycoside Antibiotics
批准号:
10653587
负责人:
Erika A Taylor
金额:
$47.47万
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
项目状态:
未结题
起止时间:
2023-07-01 至 2026-06-30
关键词:
Active SitesAffinityAminesAminoglycoside AntibioticsAminoglycosidesAnti-Bacterial AgentsAntibiotic ResistanceAntibioticsAptitudeBacterial InfectionsBig DataBig Data MethodsBindingBinding SitesBiochemicalBiochemistryBiological AssayBiophysicsCalcium ChannelCationsCell FractionCell membraneCellsChargeChemistryCollaborationsComputing MethodologiesDataDevelopmentDockingDrug DesignEnsureEnzymesEscherichia coliEscherichia coli ProteinsEvaluationEventFluorescenceFutureGel ChromatographyGoalsGram-Negative BacteriaHumanIn VitroInvestigationKineticsKnowledgeLibrariesLigand BindingLipopolysaccharide Biosynthesis PathwayMass Spectrum AnalysisMethodsMicrobial Drug ResistanceModificationMorbidity - disease rateMutagenesisPermeabilityPharmaceutical PreparationsPhenotypePhosphorylasesProtein AnalysisProtein BiosynthesisProteinsRNA chemical synthesisResearchRibosomesScienceSpectrum AnalysisStatistical Data InterpretationStatistical MethodsStructure-Activity RelationshipStudent recruitmentStudentsTestingToxic effectTrainingUniversitiesWorkX-Ray Crystallographyamidasebactericidecellular targetingchemical groupcohortcomparativecomputer studiesdesigndrug discoveryeffective therapyexperimental studyguanidiniumin silicoinhibitorintermolecular interactionmolecular dynamicsmolecular recognitionmortalitynanomolarnephrotoxicitynew therapeutic targetnovelototoxicitypriority pathogenprotein expressionprotein functionprotein structureresponseside effectstructural biologystudent trainingsuccesssynergismundergraduate student
中文摘要
项目摘要
由于许多革兰氏阴性细菌物种表现出抗菌药物耐药性,
新的抑制剂和现有抑制剂的优化是必要的,以使有效的治疗,
疾病。我们实验室和其他实验室的最新研究成果表明,氨基糖苷类药物具有最小的
影响蛋白质合成,事实上,它们在大肠杆菌中有效地与庚糖基转移酶I(HepI)结合。这
这是一个重要的发现,因为它可能会使这类抗生素得到显着的重新设计,
副作用较少的药物,因为HepI和核糖体结合位点的大小非常不同,
在电荷上有很大的差异(HepI带正电荷,而核糖体带负电荷)。这
一项提案将推动重新设计氨基糖苷类抗生素的努力,以增强HepI的结合,
与其他细胞靶点结合,可能导致耳毒性和肾毒性等副作用。
我们的研究将解决三个假设:(1)氨基糖苷类药物结合到其他细胞靶点,
核糖体包括庚糖基转移酶,(2)理解HepI-氨基糖苷相互作用
将使结构修饰和杀菌活性的优化成为可能,以及(3)计算方法
可以促进氨基糖苷类药物的重新设计。迄今为止,重新设计氨基糖苷类以更有效地结合
核糖体未能导致更有效的药物,这可能是因为作用机制涉及
其他酶如HepI。这项工作有望加强药物发现的努力,同时也提供培训,
我实验室的学生和卫斯理大学的两个高级生物化学课程的学生,在21世纪的世纪药物发现
方法.
英文摘要
Project Summary
With numerous Gram-negative bacterial species demonstrating antimicrobial drug resistance, the identification
of new inhibitors and the optimization of existing inhibitors is necessary to enable an effective treatment of
illnesses. Recent research efforts in our lab and others have demonstrated that aminoglycosides have minimal
impact on protein synthesis and in fact they potently bind to heptosytransferase I (HepI) in Escherichia coli. This
is an important finding, because it may allow for this class of antibiotics to be dramatically redesigned to be better
drugs with fewer side effects, because the HepI and ribosome binding sites have very different sizes and they
have dramatic differences in charges (HepI is positively charged, while the ribosome is negatively charged). This
proposal will advance efforts to redesign aminoglycoside antibiotics to enhance HepI binding and to reduce
binding to other cellular targets that can lead to side effects like oto- and nephrotoxicity.
Our investigation will address three hypotheses: (1) that aminoglycosides bind to other cellular targets beyond
the ribosome including heptosyltransferase enzymes, (2) understanding the HepI-aminoglycoside interactions
will enable structural modification and optimization of bactericidal activity, and (3) that computational methods
can enhance aminoglycoside redesign. To date, efforts to redesign aminoglycosides for more potent binding to
the ribosome has failed to lead to more potent drugs, and this is likely because the mechanism of action involves
other enzymes like HepI. This work promises to enhance drug discovery efforts while also providing training for
students in my lab and in two upper-level biochemistry courses at Wesleyan in 21st century drug discovery
methods.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Inhibition of HeptosyltransferaseI for the treatment of Gram-negative bacterial infection
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批准号:8958425
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项目类别:
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资助金额:$49.29万
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财政年份:2015
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负责人:Erika A Taylor
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依托单位:
海外基金