Novel Mechanisms of Beta-lactam Resistance in Staph Aureus

金黄色葡萄球菌β-内酰胺耐药的新机制

基本信息

  • 批准号:
    8507836
  • 负责人:
  • 金额:
    $ 39.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-01 至 2012-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): We have discovered a novel mechanism (or mechanisms) of resistance to ?-lactams that is independent of the two known mechanisms of staphylococcal resistance to beta-lactams: pencillinase and PBP2a. This type of resistance was identified during experiments in which a methicillin-susceptible S. aureus strain was passaged in the presence of a so-called "fifth generation" anti-MRSA cephalosporin, ceftobiprole. Whole genome sequencing of a resistant mutant revealed mutations in genes encoding the following proteins: PBP4, a non-essential, low-molecular weight penicillin-binding protein; GdpP, a putative signaling protein; and AcrB, a putative transporter. We hypothesize that mutations in one or more of these genes confer high-level ?-lactam resistance. To test this hypothesis, three specific aims are proposed. Aim 1: To determine which mutations in pbp4 confer high-level ?-lactam resistance. pbp4 missense mutations will be repaired using a standard allelic replacement mutagenesis protocol; repaired strains will be compared to the parent for changes in ?- lactam resistance. Alternatively, mutations will be introduced into susceptible S. aureus strains to determine the effect on susceptibility. ?-lactam antibiotic binding and enzymatic functions of PBP4 will also be assayed. Aim 2: To determine the role of gdpP in mediating susceptibility and resistance to ?-lactam antibiotics. Mutation in gdpP is associated with increased expression of pbp4 and with resistance to ?-lactams. The genetic approach described above will be used to determine whether GdpP regulates expression of pbp4 and whether GdpP impacts resistance by pbp4 or other mechanisms. Aim 3: To identify other non-mecA genes that mediate ?-lactam antibiotic resistance. Besides pbp4 and gdpP, a missense mutation was identified in arcB of the resistant mutant. Its contribution to resistance is not known. Allelic replacement experiments will be performed to determine whether AcrB regulates pbp4 expression or influences resistance phenotype. Whole genome resequencing of another ceftobiprole passage mutant, SRB, which also has pbp4 mutations but no mutations in gdpP or acrB, will be performed to identify other mutations that contribute to resistance. The overall goal of the proposed research is to define the molecular basis for mecA-independent resistance to ?-lactams, which could lead to a better understanding of ?-lactam antibiotic effects and identification of novel drug targets.
描述(由申请人提供):我们发现了一种(或多种)抗?-内酰胺独立于葡萄球菌对-内酰胺耐药的两种已知机制:铅笔酶和PBP2a。这种类型的耐药是在实验中发现的,在实验中,一种对甲氧西林敏感的金黄色葡萄球菌菌株在所谓的“第五代”抗mrsa头孢菌素ceftobiprole的存在下传代。抗性突变体的全基因组测序显示编码以下蛋白质的基因发生突变:PBP4,一种非必需的低分子量青霉素结合蛋白;GdpP,一种假定的信号蛋白;以及AcrB,一种假定的转运蛋白。我们假设这些基因中的一个或多个突变赋予了高水平?内酰胺阻力。为了验证这一假设,提出了三个具体目标。目的1:确定哪些pbp4突变导致高水平?内酰胺阻力。Pbp4错义突变将使用标准的等位基因替换突变方案进行修复;将修复菌株与母株进行比较,以确定?-耐内酰胺。或者,将突变引入易感金黄色葡萄球菌菌株,以确定对易感性的影响。?还将检测PBP4的-内酰胺类抗生素结合和酶功能。目的2:确定gdpP在介导对?内酰胺抗生素。gdpP的突变与pbp4的表达增加和对-内酰胺的抗性有关。上述遗传方法将用于确定GdpP是否调节pbp4的表达,以及GdpP是否通过pbp4或其他机制影响抗性。目的3:鉴定介导?-内酰胺类抗生素耐药性。除了pbp4和gdpP外,在抗性突变体的arcB中还发现了一个错义突变。它对耐药性的贡献尚不清楚。将进行等位基因替换实验,以确定AcrB是否调节pbp4的表达或影响抗性表型。将对另一种头孢双prole传代突变体SRB进行全基因组重测序,该突变体也有pbp4突变,但没有gdpP或acrB突变,以确定导致耐药性的其他突变。总体目标

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Binh An Diep其他文献

Treatment Efficacy of MEDI3902 in Pseudomonas aeruginosa Bloodstream Infection and Acute Pneumonia Rabbit Models
  • DOI:
    10.1128/aac.00710-19
  • 发表时间:
    2019-08-01
  • 期刊:
  • 影响因子:
    4.9
  • 作者:
    Le, Hoan N.;Tran, Vuvi G.;Binh An Diep
  • 通讯作者:
    Binh An Diep
Concurrent Epidemics of Skin and Soft Tissue Infection and Bloodstream Infection Due to Community-Associated Methicillin-Resistant Staphylococcus aureus
  • DOI:
    10.1093/cid/cis527
  • 发表时间:
    2012-09-15
  • 期刊:
  • 影响因子:
    11.8
  • 作者:
    Tattevin, Pierre;Schwartz, Brian S.;Binh An Diep
  • 通讯作者:
    Binh An Diep
Clonal Composition and Community Clustering of Drug-Susceptible and -Resistant Escherichia coli Isolates from Bloodstream Infections
  • DOI:
    10.1128/aac.01025-12
  • 发表时间:
    2013-01-01
  • 期刊:
  • 影响因子:
    4.9
  • 作者:
    Adams-Sapper, Sheila;Binh An Diep;Riley, Lee W.
  • 通讯作者:
    Riley, Lee W.

Binh An Diep的其他文献

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{{ truncateString('Binh An Diep', 18)}}的其他基金

Mechanisms of PVL-induced Acute Lung Injury
PVL引起的急性肺损伤的机制
  • 批准号:
    8277422
  • 财政年份:
    2010
  • 资助金额:
    $ 39.14万
  • 项目类别:
Mechanisms of PVL-induced Acute Lung Injury
PVL引起的急性肺损伤的机制
  • 批准号:
    8089592
  • 财政年份:
    2010
  • 资助金额:
    $ 39.14万
  • 项目类别:
Mechanisms of PVL-induced Acute Lung Injury
PVL引起的急性肺损伤的机制
  • 批准号:
    8464624
  • 财政年份:
    2010
  • 资助金额:
    $ 39.14万
  • 项目类别:
Mechanisms of PVL-induced Acute Lung Injury
PVL引起的急性肺损伤的机制
  • 批准号:
    8665795
  • 财政年份:
    2010
  • 资助金额:
    $ 39.14万
  • 项目类别:
Mechanisms of PVL-induced Acute Lung Injury
PVL引起的急性肺损伤的机制
  • 批准号:
    7992854
  • 财政年份:
    2010
  • 资助金额:
    $ 39.14万
  • 项目类别:

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