Combating Mult-Drug Resistant Bacteria
对抗多重耐药细菌
基本信息
- 批准号:7218108
- 负责人:
- 金额:$ 19.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-04-15 至 2008-03-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAffinityAmino AcidsAminoglycoside AntibioticsAminoglycosidesAntibiotic ResistanceAntibioticsBacteriaBacterial Antibiotic ResistanceBacterial Drug ResistanceBindingBinding SitesBiologicalBiological AssayCatalysisCellsChargeClassClassificationCloningCollectionCommunitiesDNADNA BindingDNA biosynthesisDevelopmentDisruptionElementsEnzymesGene MutationGenesGenus staphylococcusHealthHospitalsHumanIn VitroInfectionInheritedInvestigationLeadLibrariesLifeMacrolidesMass Spectrum AnalysisMediatingMediator of activation proteinMessenger RNAMethicillin ResistanceModificationMulti-Drug ResistanceNatureNumbersPlasmidsPositioning AttributePropertyProteinsPublic HealthRNARNA BindingReactionReplication InitiationReporter GenesReportingResistanceRoleSiteSite-Directed MutagenesisStretchingSystemTherapeutic AgentsTimeTyrosineVancomycin resistant enterococcusVertebral columnWorkX-Ray Crystallographyanalogappendagebacterial resistancebasebeta-Lactamscombinatorialconceptdesigndrug resistant bacteriads-DNAenzyme activityenzyme mechanismin vivoinhibitor/antagonistinorganic phosphatenovel strategiesphosphoric diester hydrolaseresearch studysmall moleculestemthree dimensional structuretool
项目摘要
DESCRIPTION (provided by applicant): Bacterial resistance to antibiotics has emerged as a considerable threat to human health. Methicillin-resistant Staphloccous aureus (MRSA) and vancomycin-resistant enterococci (VRE) are multi-drug resistant bacteria that cause life threatening infections in the hospital setting and in some cases have leapt to the larger community. It is clear that new strategies and tactics are needed to combat these insidious bacteria. Often times, bacteria owe their antibiotic resistance to the proteins encoded by plasmids that they harbor. Plasmids are small, circular, extra-chromosomal pieces of DNA that can be transferred from one bacterium to another. These plasmids often contain genes that encode proteins that confer resistance to a wide array of antibiotics. Indeed, for several classes of antibiotics (including beta-lactams, macrolides, and aminoglycosides) plasmid-borne resistance is ubiquitous. In addition, many of the worst multi-drug resistant bacteria (including MRSA and VRE) are resistant by virtue of the plasmid they harbor. Proposed herein is a strategy to attack this plasmid-encoded resistance through the creation of "anti-plasmid" agents, small molecules that will vanquish the plasmid from the cell, thus rendering the bacteria sensitive to antibiotics. These compounds are designed to mimic a known, naturally occurring mechanism for plasmid elimination, known as plasmid incompatibility. The bio-molecules that determine plasmid incompatibility are typically small pieces of RNA and DNA iterons. It has been shown that genetic mutation of these RNA incompatibility determinants disrupts RNA loop-loop interactions and leads to plasmid elimination. In Specific Aims 1 and2 of this proposal, small molecules are described that will disrupt the RNA loop-loop interaction in a completely analogous manner, thus leading to plasmid elimination. Specific Aims 3 and 4 describe studies on the mechanism and inhibition of the plasmid replication initiation protein, RepA. The successful completion of the experiments described herein could lead to a dramatic change in the manner in which antibiotic resistant infections are treated.
描述(申请人提供):细菌对抗生素的耐药性已成为对人类健康的相当大威胁。耐甲氧西林金黄色葡萄球菌(MRSA)和万古霉素耐药肠球菌(VRE)是多重耐药细菌,在医院环境中会导致危及生命的感染,在某些情况下已经蔓延到更大的社区。显然,需要新的战略和战术来打击这些潜伏的细菌。细菌对抗生素的抗药性往往归功于它们所携带的质粒所编码的蛋白质。质粒是微小的、环形的、染色体外的DNA片段,可以从一种细菌转移到另一种细菌。这些质粒通常含有编码蛋白质的基因,这些蛋白质能对多种抗生素产生耐药性。事实上,对于几类抗生素(包括β-内酰胺类、大环内酯类和氨基糖苷类)来说,质粒携带的耐药性是普遍存在的。此外,许多最严重的多重耐药细菌(包括耐甲氧西林金黄色葡萄球菌和VRE)凭借它们所携带的质粒而产生耐药性。这里提出了一种策略,通过创建“反质粒”制剂来攻击这种由质粒编码的耐药性,这种小分子将从细胞中消灭质粒,从而使细菌对抗生素敏感。这些化合物被设计成模仿一种已知的、自然发生的消除质粒的机制,即所谓的质粒不相容。决定质粒不亲和性的生物分子通常是小片段的RNA和DNA迭代。已有研究表明,这些RNA不相容决定因素的基因突变会破坏RNA环-环相互作用,并导致质粒消除。在本提案的具体目标1和2中,描述了小分子将以完全类似的方式破坏RNA环-环相互作用,从而导致质粒消除。具体目标3和4描述了关于质粒复制起始蛋白REPA的机制和抑制的研究。这里描述的实验的成功完成可能会导致抗生素耐药感染的治疗方式发生巨大变化。
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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Paul Hergenrother其他文献
Paul Hergenrother的其他文献
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