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Gene transfer and the evolution of penicillin resistance: PBPs and non-PBP genes in laboratory mutants and clinical isolates in Streptococcus pneumoniae

基因转移和青霉素耐药性的进化：肺炎链球菌实验室突变体和临床分离株中的 PBP 和非 PBP 基因

基本信息

批准号：
73111189
负责人：
Professorin Dr. Regine Hakenbeck
金额：
--
依托单位：
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/73111189?language=en
关键词：
Gene transfer evolution penicillin resistance

项目摘要

Multiple players are involved in the development of beta-lactam resistance in Streptococcus pneumoniae. Most importanta are the target enzymes of these antibiotics, the penicillin-binding proteins (PBPs). Alterations in at least three PBPs are required to achieve high resistance level. In particular clinical isolates MurM is also altered, conferring resistance in the presence of PBPs. PBPs are the main transpeptidases responsible for crosslinkage of the peptidoglycan subunits, and MurM modifies these subunits and contributes to the synthesis of interpeptide bridges. In resistant laboratory mutants, the two component system CiaRH is activated via mutations in the histidine protein kinase CiaH. We have recently shown that the cell wall associated serine protease/chaperone HtrA which is part of the Cia regulon targets GFP-BP2x derivatives. Moreover, the biosynthesis of the major glycolipid in pneumococci is affected by mutations in the glycosyltransferase CpoA. All these components are important for cell growth and division, and several of them have been shown to localize to septal sites such as PBP2x, PBP1a, HtrA and as will be shown here also CiaH.The current proposal is related to the interplay of these components during the development of beta-lactam resistance. One part concerns mutations that occurred during transformation of S. pneumoniae using DNA of high level resistant commensal species. In a second series of experiments, the contribution of genes known to be involved in the resistance phenotype is analyzed in one partFP-icular resistant clone of S. pneumoniae Hungary19A-6. In this clone, murM and ciaH are altered in addition to three PBPs. Finally experiments concerning the localization of PBP2x using GFP-fusion proteins are described, including quality control of PBP2x mutants by the cell wall protease HtrA.

多重因素参与了肺炎链球菌β-内酰胺耐药性的发展。最重要的是这些抗生素的靶酶，青霉素结合蛋白（PBP）。至少需要改变三个PBPs以实现高抗性水平。特别是临床分离株MurM也发生了改变，在存在PBPs的情况下产生了耐药性。PBP是负责肽聚糖亚基交联的主要转肽酶，MurM修饰这些亚基并有助于肽间桥的合成。在抗性实验室突变体中，双组分系统CiaRH通过组氨酸蛋白激酶CiaH中的突变被激活。我们最近已经表明，细胞壁相关的丝氨酸蛋白酶/伴侣蛋白HtrA是Cia调节子的一部分，其靶向GFP-BP 2x衍生物。此外，肺炎球菌中主要糖脂的生物合成受到糖基转移酶CpoA突变的影响。所有这些组分对于细胞生长和分裂都是重要的，并且已经显示其中的几种定位于隔膜位点，例如PBP 2x、PBP 1a、HtrA，并且如这里将显示的，还有CiaH。一部分涉及S.肺炎克雷伯氏菌使用高水平耐药菌种的DNA。在第二系列实验中，在S的一个特定FP抗性克隆中分析了已知参与抗性表型的基因的贡献。pneumoniae Hungary19A-6.在该克隆中，除了三个PBP之外，murM和ciaH也被改变。最后，关于使用GFP融合蛋白定位PBP 2x的实验进行了描述，包括通过细胞壁蛋白酶HtrA对PBP 2x突变体进行质量控制。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transfer of penicillin resistance from Streptococcus oralis to Streptococcus pneumoniae identifies murE as resistance determinant

DOI：
10.1111/mmi.13070
发表时间：
2015-09
期刊：
Molecular Microbiology
影响因子：
3.6
作者：
K. Todorova;P. Maurer;M. Rieger;T. Becker;N. K. Bui;J. Gray;W. Vollmer;R. Hakenbeck
通讯作者：
K. Todorova;P. Maurer;M. Rieger;T. Becker;N. K. Bui;J. Gray;W. Vollmer;R. Hakenbeck

Genomics, Genetic Variation, and Regions of Differences

基因组学、遗传变异和差异区域

DOI：
10.1016/b978-0-12-410530-0.00005-3
发表时间：
2015
期刊：
影响因子：
0
作者：
Tettelin;S. Chancey;T. Mitchell;D. Denapaite;Y. Schähle;M. Rieger;R. Hakenbeck
通讯作者：
R. Hakenbeck

Penicillin-binding protein 2x of Streptococcus pneumoniae: the mutation Ala707Asp within the C-terminal PASTA2 domain leads to destabilization.

肺炎链球菌青霉素结合蛋白 2x：C 端 PASTA2 结构域内的 Ala707Asp 突变导致不稳定