DISSEMINATION OF MACROLIDE RESISTANCE ELEMENTS IN STREPTOCOCCUS PNEUMONIAE

肺炎链球菌中大环内酯类耐药元件的传播

• 批准号: 9888324
• 负责人: DAVID S STEPHENS
• 金额: $ 16.41万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888324
• 关键词: Address; Antibiotic Resistance; Antibiotics; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Chromosomes; Clinical; Clonal Expansion; Competence; Complex; DNA; DNA Transposons; Data; Elements; Engineering; Environment; Epidemiology; Epithelial; Epithelium; Frequencies; Gene Transfer; Genetic; Genetic Determinism; Genetic Recombination; Genome; Genomics; High Prevalence; Hot Spot; Human; Individual; Intervention; Investigation; Macrolide-resistance; Macrolides; Mediating; Microbial Biofilms; Mobile Genetic Elements; Molecular; Movement; Multi-Drug Resistance; Nasopharynx; Nature; Pneumococcal Infections; Population; Prevalence; Proteins; Recombinants; Resistance; Ribosomes; Serotyping; Site; Source; Streptococcus pneumoniae; Surface; Virulent; World Health Organization; clinically relevant; design; early childhood; emerging antimicrobial resistance; epidemiology study; genomic locus; human model; insight; mutant; novel; pathogen; pressure; priority pathogen; recombinase; respiratory; tRNA Methyltransferases

Abstract Streptococcus pneumoniae (Spn) colonizes the epithelial surface of the human nasopharynx in early childhood and remains a significant cause of respiratory illness. Globally, Spn causes 15 million cases of pneumococcal disease (PD) each year leading to approximately ∼0.5 million deaths in children. Treatment of PD has been hindered by emergence of antimicrobial resistance, including the resistance to macrolides. Most pneumococcal macrolide resistance is conferred by Erm(B), the RNA methylase, and/or efflux/ribosomal protection mediated by Mef(E)/Mel on the macrolide efflux genetic assembly (Mega) element. The Mega element, related to Tn916 conjugative transposons but does not encode putative recombinases, has integrated into at least four loci in the pneumococcal chromosome, Mega classes I–IV. Molecular epidemiological studies demonstrated a higher prevalence of isolates containing the class II Mega, which is not caused by clonal expansion. Moreover, a wide array of complex Tn916 related mobile genetic elements, termed integrative and conjugative elements (ICEs), has emerged that also facilitate dissemination of macrolide resistance (both ermB and Mega) and additional antibiotic resistance markers. While acquisition of Mega and ICE-encoded resistance presumably occurs during colonization of the human nasopharynx, the efficiency and the specific mechanisms by which Mega elements and ICEs spread among pneumococci in the nasopharynx is not well understood. Our novel discovery of pneumococcal unidirectional transformation in the human nasopharyngeal biofilms has provided new insights on gene transfer in S. pneumoniae. In this proposal, using an established model of human nasopharyngeal consortial biofilms and the newly characterized uni-directional gene transfer phenomenon, we will determine the mechanisms and frequencies of macrolide resistance dissemination mediated by the Mega elements and ICEs. In Aim 1 we will evaluate whether genomic recombination hot spots or strain background, influence the recombination frequency (rF) and account for different prevalence among Mega classes. Donor strains engineered with each of the four Mega classes and defined pneumococcal clinical isolates containing the Mega classes will be conducted to assess the contribution of genomic loci and strain backgrounds, respectively. Both the rF and the specific recombination sites will be defined in recombinants. In aim 2 we will investigate whether conjugation or recombination via transformation, drives the mobilization of ICE- encoded macrolide resistant determinants. The molecular mechanism of ICE-dissemination among pneumococci will be further investigated using mutants with inactivated transposon-encoded mobilization proteins and proteins mediating competence. Identifying the horizontal dissemination mechanisms and frequencies of the two-major macrolide resistance genetic determinants will be valuable for new interventions aimed at decreasing the burden of antibiotic resistance dissemination in S. pneumoniae.

摘要 肺炎链球菌(Spn)在人鼻咽上皮细胞表面定植 儿童早期感染，仍然是呼吸系统疾病的一个重要原因。在全球范围内，Spn导致1500万例 肺炎球菌病(PD)每年导致大约50万儿童∼死亡。帕金森病的治疗 由于出现了抗菌素耐药性，包括对大环内酯类药物的耐药性，这种耐药性受到了阻碍。多数 肺炎球菌对大环内酯类抗生素耐药与Erm(B)、RNA甲基酶和/或外排/核糖体有关 MEF(E)/MEL对大环内酯类外排遗传组件(MEGA)元件的保护作用《巨无霸》 与Tn916接合转座子相关但不编码可能的重组酶的元件已经整合 在肺炎球菌染色体上至少有四个基因座，Mega I-IV类。分子流行病学研究 显示含有II类MegA的分离物的流行率较高，这不是由克隆引起的 扩张。此外，一系列与Tn916相关的复杂移动遗传元件被称为整合和 结合元件(ICE)的出现，也促进了大环内酯类耐药性的传播(两者都是ermB 和Mega)和其他抗生素耐药性标记。同时采集Mega和ICE编码的电阻 推测发生在人类鼻咽定植期间的效率和具体机制 Mega元素和冰是如何在鼻咽肺炎球菌之间传播的还不是很清楚。我们的 人鼻咽生物膜中肺炎链球菌单向转化的新发现 为肺炎链球菌的基因转移提供了新的见解。在本提案中，使用已建立的模型 人鼻咽结合生物膜与新发现的单向基因转移 我们将确定大环内酯类耐药性传播的机制和频率。 由Mega Elements和ICES调停。在目标1中，我们将评估基因组重组热点 或菌株背景，影响重组频率(Rf)，并解释不同的患病率 超大班级。与四个Mega类别中的每一个一起工程的供体菌株和确定的肺炎球菌临床 含有Mega类的分离株将被用于评估基因组座位和菌株的贡献。 背景分别为。Rf和特定重组位点都将在重组子中定义。在……里面 目的2我们将研究是否通过转化的接合或重组，驱动ICE- 编码的大环内酯类抗药性决定因素。冰川传播的分子机制 肺炎球菌将使用具有灭活转座子编码动员的突变体进行进一步研究 蛋白质和调节能力的蛋白质。确定水平传播机制和 两种主要的大环内酯耐药基因决定因素的频率对新的干预措施将是有价值的 旨在减轻肺炎链球菌耐药性传播的负担。

项目成果

Hydrogen Peroxide Production by Streptococcus pneumoniae Results in Alpha-hemolysis by Oxidation of Oxy-hemoglobin to Met-hemoglobin.

• DOI: 10.1128/msphere.01117-20
• 发表时间: 2020-12-09
• 期刊: mSphere
• 影响因子: 4.8
• 作者: McDevitt E;Khan F;Scasny A;Thompson CD;Eichenbaum Z;McDaniel LS;Vidal JE
• 通讯作者: Vidal JE