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.

抽象的 肺炎链球菌 (Spn) 定植于人鼻咽部的上皮表面 Spn 仍然是儿童早期呼吸系统疾病的一个重要原因，导致 1500 万例呼吸道疾病。 肺炎球菌疾病 (PD) 每年导致大约 50 万名儿童死亡。 抗菌药物耐药性的出现阻碍了这一进程，其中包括对大环内酯类药物的耐药性。 肺炎球菌大环内酯类耐药性是由 Erm(B)、RNA 甲基化酶和/或外排/核糖体赋予的 Mef(E)/Mel 对大环内酯外流基因组装 (Mega) 元件的保护作用。 与 Tn916 接合转座子相关但不编码假定的重组酶的元件已整合 进入肺炎球菌染色体中的至少四个基因座，Mega I-IV 类分子流行病学研究。 含有 II 类 Mega 的分离株的患病率较高，这不是由克隆引起的 此外，一系列复杂的 Tn916 相关的可移动遗传元件被称为整合和扩展。 共轭元件（ICE）的出现也促进了大环内酯类耐药性的传播（ermB 和 Mega）以及其他抗生素抗性标记，同时获得 Mega 和 ICE 编码的抗性。 推测是在人鼻咽定植过程中发生的，其效率和具体机制 巨型元素和 ICE 在鼻咽部肺炎球菌中传播的方式尚不清楚。 肺炎球菌在人鼻咽生物膜中单向转化的新发现 在本提案中，使用已建立的模型，提供了有关肺炎链球菌基因转移的新见解。 人鼻咽联合生物膜和新特征的单向基因转移 现象，我们将确定大环内酯类耐药性传播的机制和频率 在目标 1 中，我们将评估是否存在基因组重组热点。 或菌株背景，影响重组频率（rF）并解释不同流行率 Mega 类别。供体菌株采用四种 Mega 类别和定义的肺炎球菌临床设计。 将进行包含 Mega 类的分离株以评估基因组位点和菌株的贡献 rF 和特定重组位点将分别在重组体中定义。 目标 2 我们将研究通过转化进行的缀合或重组是否会驱动 ICE-的动员 编码的大环内酯类耐药决定因素。 将使用具有失活转座子编码动员的突变体进一步研究肺炎球菌 确定蛋白质和蛋白质介导能力。 两种主要大环内酯类耐药遗传决定因素的频率对于新的干预措施将很有价值 旨在减轻肺炎链球菌抗生素耐药性传播的负担。

项目成果

Limited protection of pneumococcal vaccines against emergent Streptococcus pneumoniae serotype 14/ST876 strains.

肺炎球菌疫苗对新出现的肺炎链球菌血清型 14/ST876 菌株的保护有限。

• 发表时间: 2023-11-02
• 影响因子: 7.5
• 作者: Lan, Yinle;Liu, Lin;Hu, Dongping;Ge, Lihong;Xiang, Xi;Peng, Minfei;Fu, Ying;Wang, Yanfei;Li, Shuxian;Chen, Yan;Jiang, Yan;Tu, Yuexing;Vidal, Jorge E;Yu, Yunsong;Chen, Zhimin;Wu, Xueqing
• 通讯作者: Wu, Xueqing

Pneumococcal Carriage Among Indigenous Kichwa Children From the Ecuadorian Andes After the 10-Valent Pneumococcal Vaccine Introduction.

引进 10 价肺炎球菌疫苗后，厄瓜多尔安第斯山脉土著 Kichwa 儿童中的肺炎球菌携带情况。

• 发表时间: 2021-11-01
• 作者: Regalado L, Daniela;Rivera;Garcia;Tana, Leandro;Hernandez, Isabel;Zurita, Jeannete;Vidal, Jorge E;Terán, Enrique;de Waard, Jacobus H
• 通讯作者: de Waard, Jacobus H

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

肺炎链球菌产生的过氧化氢通过氧合血红蛋白氧化成高铁血红蛋白而导致α溶血。

• 发表时间: 2020
• 影响因子: 4.8
• 作者: McDevitt, Erin;Khan, Faidad;Scasny, Anna;Thompson, Courtney D;Eichenbaum, Zehava;McDaniel, Larry S;Vidal, Jorge E
• 通讯作者: Vidal, Jorge E

Editorial: Transmission, colonization, and molecular pathogenesis of pneumococcus.

社论：肺炎球菌的传播、定植和分子发病机制。

• 发表时间: 2022
• 作者: Vidal, Jorge E;Bou Ghanem, Elsa N;Wu, Xueqing;Wu, Kaifeng;Bai, Guangchun;Hammerschmidt, Sven
• 通讯作者: Hammerschmidt, Sven