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
基本信息
- 批准号:8557227
- 负责人:
- 金额:$ 38.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-05-24 至 2017-04-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAbscessAccident and Emergency departmentAcuteAnti-Bacterial AgentsAntibioticsAntitoxinsBacteriaBacterial PhysiologyBindingBiogenesisBoxingCaringCell DeathCell FractionationCell WallCellsCephalosporinsCessation of lifeCleaved cellClinicComplexCoupledDNA GyraseDaptomycinDataDetectionDevelopmentDigestionDropsEndoribonucleasesEscherichia coliFractionationGenesGenomeGoalsGrowthHeparinHospitalsHourHousekeepingIn VitroIndividualInfectionInfectious Skin DiseasesLabelLeadLinezolidLinkMediatingMessenger RNAMetabolicMethicillinMethyltransferaseMindModelingMusNamesNormalcyNutrientOxacillinPaperParentsPeptide HydrolasesProcessProkaryotic CellsProtein SProtein Synthesis InhibitionProteinsPublishingRNARNA HelicaseRNA-Binding ProteinsRadiolabeledResistanceRibonucleasesRibosomesRoleSiteSpecificityStaining methodStainsStaphylococcus aureusStressSystemToxinTranslatingUnited StatesValidationVancomycinantimicrobial drugbacterial resistancebasecellular targetingcopingdrug discoveryempoweredendonucleaseendoribonucleasehelicasein vivoinsightinterestkillingsmRNA DecaymRNA Transcript Degradationmethicillin resistant Staphylococcus aureusmutantnovelnovel strategiespathogenpathogenic bacteriapublic health relevanceradiotracerresponseribonuclease E
项目摘要
DESCRIPTION (provided by applicant): S. aureus bacteria are commonly resistant to methicillin and other cell-wall active antibiotics. The goal of this application is to validate the
MazF toxin and specific RNA binding proteins of S. aureus that interfere with specific mRNA degradation as novel targets for antibacterial drug discovery. Toxin antitoxin systems (TA) are common in bacteria. Among the different TA modules that are protein-based, the MazEF system is by far the best characterized. In prior papers that we have published, we have shown that that the MazFsa toxin of S. aureus is a specific endoribonuclease that cuts at the VUUV' site where V or V' can be A, C or G, leading to inhibition of protein synthesis and the ensuing growth arrest.
The MazFsa-mediated growth arrest is unique because these cells are viable but cannot replicate. To delineate this unique form of growth arrest, we have shown that MazFsa cleaves most of the cellular mRNAs but spares some housekeeping (e.g. recA, gyrB) and a global regulator (sarA) mRNAs, presumably allowing the bacterium to enter metabolic quiescence without sacrificing viability. We hypothesize that specific RNA-binding protein(s) may protect some of these "important" mRNAs" under MazFsa-mediated stress. A corollary of our hypothesis is that inactivation of these "specific RNA binding proteins", coupled with MazFsa activation, will promote cell death rather than growth arrest since these "essential" mRNA will no longer be protected. Cell fractionation analysis, coupled with Northwestern blots with a labeled sarA mRNA probe, have enabled us to identify CshA, CshB and SA1641 as putative "RNA-binding proteins". CshA and CshB are potential DEAD-box RNA helicases while SA1641 has homology with RNA methyltransferase. Previously, DEAD-box proteins have been known to participate in ribosome biogenesis and mRNA decay. Thus, protection of mRNAs from MazFsa-mediated cleavage by CshA and CshB will be a novel concept for DEAD-box proteins. To validate the above hypotheses, we have developed the following specific aims: I) defining the ability of CshA and CshB to bind and protect selective mRNAs from MazFsa-mediated degradation in vitro; II) assessing the degradation of selective MRNA in single and double cshA and cshB mutants, the viability of these mutants upon MazFsa induction and their sensitivity to selective antibiotics; III) characterization of other factors (e.g. SA1641) that help protect selective mRNA from MazFsa-mediated degradation; IV) evaluating the survival of single and double cshA and cshB mutants with and without MazFsa induction in murine models of infection. The results of these studies will allow us to validate the novel function of DEAD-box and other unique RNA-binding proteins in S. aureus. These studies will also provide us with the validation that activation of MazFsa, coupled with inactivation of CshA, CshB, SA1641 and/or other factors, is a novel approach to kill MSSA and MRSA. Accordingly, MazFsa and "specific RNA binding proteins" represent novel targets for antibiotic development. As TA systems, DEAD-box and other RNA binding proteins are common in prokaryotes, our results may apply to other pathogens.
描述(由申请人提供):金黄色葡萄球菌通常对甲氧西林和其他细胞壁活性抗生素耐药。此应用程序的目标是验证
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:
$ 38.05万 - 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:
10563142 - 财政年份:2020
- 资助金额:
$ 38.05万 - 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:
$ 38.05万 - 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:
$ 38.05万 - 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:
$ 38.05万 - 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:
$ 38.05万 - 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:
$ 38.05万 - 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:
$ 38.05万 - 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:
$ 38.05万 - 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:
$ 38.05万 - 项目类别:
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