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The role of purine biosynthesis and stringent response in persistent MRSA endovascular infections

嘌呤生物合成和严格反应在持续性 MRSA 血管内感染中的作用

基本信息

批准号：
10543433
负责人：
YAN Q. XIONG
金额：
$ 45.08万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-14 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543433
关键词：
ATP Synthesis Pathway Anabolism Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteremia Bacteria Bacterial DNA Biological Blood Clinical Communities Complement Cytolysis DNA biosynthesis Daptomycin Data Deletion Mutation Event FDA approved Failure Gene Expression Genes Genetic Genotype Goals Growth Guanosine Tetraphosphate Immunity In Vitro Infection Infective endocarditis Investigation Kinetics Laboratories Life Link Mediating Medical Metabolic Pathway Microbial Biofilms Modeling Molecular Morbidity - disease rate Nutrient Nutritional Outcome Paper Patients Periodicity Phase Phenols Phenotype Play Predisposition Production Public Health Publishing Purine Synthesis Inhibition Purines RNA chemical synthesis Regulation Resistance Role Signaling Molecule Staphylococcus aureus Staphylococcus aureus infection Starvation Stress Syndrome Testing Therapeutic Tissues Treatment Failure Vancomycin Variant bactericide chronic infection in vivo inhibitor inhibitor therapy methicillin resistant Staphylococcus aureus mortality mutant neutrophil novel novel strategies nutrition prototype resistance mechanism response standard of care virulence gene

项目摘要

ABSTRACT Staphylococcus aureus is the most common cause of life-threatening endovascular infection, including infective endocarditis (IE) and bacteremia. Despite the use of gold-standard antibiotics, morbidity and mortality associated with these syndromes remain unacceptably high. Emergence of methicillin-resistant S. aureus (MRSA), high rates of vancomycin (VAN) clinical failures, and rising daptomycin (DAP) resistance further emphasize this public health threat. Persistent MRSA bacteremia (PB), defined as  7 days of positive blood cultures despite appropriate antibiotic therapy, is a very worrisome sub-set of these infections. A particularly problematic metric is that PB strains are deemed “susceptible” in vitro to VAN and DAP by standard CLSI breakpoints, yet, persist in vivo despite appropriate use of these antibiotics. Therefore, PB outcomes present a unique variant of traditional antibiotic “resistance” mechanisms and significant therapeutic challenge to the medical community. Understanding the relevant molecular mechanisms of PB is essential to develop novel strategies to predict and successfully treat PB patients. Our Preliminary Data showed that the PB outcomes are likely to be multifactorial on both phenotypic and genotypic levels. Most interestingly, we have shown the impact of purine biosynthesis and stringent responses on the PB outcomes using both clinical MRSA isolates and laboratory isogenic strain sets. Based on our extensive Preliminary Data, we hypothesize that distinct regulatory cascades activated by purine biosynthesis perturbations and the stringent responses play an important role in the PB outcome. Therefore, in this proposal, we will: i) further define the impact of purine biosynthesis in the PB outcome both phenotypically and genotypically by constructing purF deletion mutations in prototypic clinical PB strains; ii) assess the role of purine biosynthesis in the stringent response as it relates to the PB outcome; iii) determine the relationship between purine biosynthesis and biofilm formation; and iv) validate the role of purine biosynthesis in the PB outcome in vivo in an experimental IE model. These studies will significantly advance our understanding on the mechanisms of persistent MRSA endovascular infection and identify unique signatures for new anti-MRSA agents or strategies to treat clinical infections featuring the PB outcome.

摘要金黄色葡萄球菌是威胁生命的血管内感染的最常见原因，包括感染性心内膜炎(IE)和菌血症。尽管使用了黄金标准的抗生素，但发病率和死亡率与这些症状相关的比例仍然高得令人无法接受。耐甲氧西林金黄色葡萄球菌的出现耐甲氧西林金黄色葡萄球菌(MRSA)，万古霉素(VAN)临床失败率高，达托霉素(DAP)耐药性进一步上升强调这一公共健康威胁。持续性耐甲氧西林金黄色葡萄球菌菌血症(PB)，定义为阳性血7天尽管进行了适当的抗生素治疗，但细菌培养是这些感染的一个非常令人担忧的子集。一个特别的问题有问题的衡量标准是，标准的CLSI认为pb菌株在体外对van和dap“敏感”。然而，尽管适当使用了这些抗生素，断点在体内仍然存在。因此，PB结果呈现出一种传统抗生素耐药机制的独特变体和对治疗的重大挑战医学界。了解PB的相关分子机制对于开发新的预测和成功治疗PB患者的策略。我们的初步数据显示，PB的结果可能是多因素的表型和基因分型水平。最有趣的是，我们已经展示了嘌呤生物合成和严格反应的影响。使用临床MRSA分离株和实验室等基因毒株集对PB结果的影响。基于我们的大量的初步数据，我们假设由嘌呤生物合成激活的不同的调节级联反应扰动和严格的响应在PB结果中起着重要作用。因此，在这份提案中，我们将：i)进一步定义嘌呤生物合成对PB结果的影响，包括表型和通过在典型的临床PB菌株中构建PurF缺失突变来进行基因分型；ii)评估严格反应中的嘌呤生物合成与PB结果有关；iii)确定关系嘌呤生物合成和生物膜形成之间的关系；以及iv)验证嘌呤生物合成在PB中的作用实验性IE模型的体内结果。这些研究将极大地促进我们对持续耐甲氧西林金黄色葡萄球菌血管内感染的机制和识别新的抗耐甲氧西林金黄色葡萄球菌的独特标志治疗以PB结果为特征的临床感染的药物或策略。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

New Mechanistic Insights into Purine Biosynthesis with Second Messenger c-di-AMP in Relation to Biofilm-Related Persistent Methicillin-Resistant Staphylococcus aureus Infections.

DOI：
10.1128/mbio.02081-21
发表时间：
2021-12-21
期刊：
mBio
影响因子：
6.4
作者：
Li L;Li Y;Zhu F;Cheung AL;Wang G;Bai G;Proctor RA;Yeaman MR;Bayer AS;Xiong YQ
通讯作者：
Xiong YQ

Transcriptome Analyses of Prophage in Mediating Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection.

DOI：
10.3390/genes13091527
发表时间：
2022-08-25
期刊：
GENES
影响因子：
3.5
作者：
Li, Yi;Chen, Liang;Zhu, Fengli;Bayer, Arnold S.;Xiong, Yan Q.
通讯作者：
Xiong, Yan Q.

Identification of Methicillin-Resistant Staphylococcus aureus (MRSA) Genetic Factors Involved in Human Endothelial Cells Damage, an Important Phenotype Correlated with Persistent Endovascular Infection.

DOI：
10.3390/antibiotics11030316
发表时间：
2022-02-26
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
0
作者：
Xiao X;Li Y;Li L;Xiong YQ
通讯作者：
Xiong YQ

The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis.

DOI：
10.1093/infdis/jiad577
发表时间：
2024-01
期刊：
The Journal of infectious diseases
影响因子：
0
作者：
Yanqiong Xiong;Yi Li;Mariya I. Goncheva;Ahmed M Elsayed;Fengli Zhu;Liang Li;W. Abdelhady;Ronald S. Flannagan;M. Yeaman;Arnold S. Bayer;D. Heinrichs
通讯作者：
Yanqiong Xiong;Yi Li;Mariya I. Goncheva;Ahmed M Elsayed;Fengli Zhu;Liang Li;W. Abdelhady;Ronald S. Flannagan;M. Yeaman;Arnold S. Bayer;D. Heinrichs