Molecular basis of decreased susceptibility to beta-lactam antibiotics in Streptococcus pyogenes

化脓性链球菌对β-内酰胺类抗生素敏感性降低的分子基础

• 批准号: 10596614
• 负责人: James MALLORY Musser
• 金额: $ 16.15万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-24 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596614
• 关键词: Accounting; Address; Amino Acids; Amoxicillin; Ampicillin; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antimicrobial susceptibility; Area; Bioinformatics; Clinical Microbiology; Collection; Communicable Diseases; Communities; Community Health; Consumption; Coupled; Data; Databases; Development; Event; Evolution; Formulation; Gene Mutation; Genes; Genetic Polymorphism; Genome; Genomics; Geography; Goals; Human; Individual; Infection; International; Knowledge; Medical; Microbiology; Molecular; Molecular Genetics; Motivation; Mutation; Organism; Paper; Pathogenicity; Patients; Penicillin-Binding Proteins; Pharyngitis; Population; Predisposition; Proteins; Public Health; Publications; Research; Research Personnel; Resistance; Resistance to infection; Resources; Role; Source; Streptococcus; Streptococcus pyogenes; Testing; United States; antimicrobial; beta-Lactam Resistance; beta-Lactams; catalyst; data resource; experience; innovation; mutant; novel; pathogen; pathogenic bacteria; prevent; repository; translational approach; treatment response

DESCRIPTIVE TITLE: Molecular basis of decreased susceptibility to beta-lactam antibiotics in Streptococcus pyogenes PROJECT ABSTRACT/SUMMARY The human bacterial pathogen Streptococcus pyogenes (group A streptococcus, GAS) causes more than 700 million human infections annually worldwide. Beta-lactam antibiotics are, and have been, the first-line treatment for GAS pharyngitis and invasive infections. For reasons that remain shrouded in mystery and speculation, this pathogen has continued to be uniformly susceptible to beta-lactam antibiotics for 70 years. However, a recent paper described two GAS infection-causing strains with significantly decreased susceptibility to the beta-lactam antibiotics ampicillin and amoxicillin, causing great concern in the United States and international infectious disease community. This revelation, coupled with our recent discovery that invasive GAS strains with significantly decreased susceptibility to beta-lactam antibiotics are far more common and geographically widespread than previously thought, have served as the catalyst for the research proposed herein. To achieve our goal of greatly enhancing current understanding of the relationship between specific gene mutations and decreased GAS beta-lactam susceptibility, the following two specific aims are proposed. Specific Aim 1: Sequence and analyze the genomes of >11,000 strains to define the spectrum of mutations present in the penicillin-binding protein 2X (pbp2x) and penicillin-binding protein 1A (pbp1A) genes in GAS recovered from pharyngitis and asymptomatic carriers. We will determine MICs for nine commonly used beta-lactams on 2,750 (25%) of the strains. Mutations in these two genes are known to confer decreased beta-lactam susceptibility in many organisms, including pathogenic streptococci. We will exploit our unique collection of 40,000 GAS strains recovered over decades from global sources. Specific Aim 2: Construct and analyze 50 isogenic mutant strains to test the hypothesis that specific naturally-occurring amino acid replacements in PBP2X and PBP1A decrease the susceptibility of GAS to beta-lactam antibiotics, as judged by MIC susceptibility analysis. The results of the studies proposed in these two aims will provide extensive unique data necessary to more fully understand the scope of this critical new antimicrobial resistance threat. It is reasonable to speculate that the resulting data may also ultimately lead to novel translational strategies to prevent, limit, and treat antibiotic-resistant GAS infections. A key motivation is to generate and make available this extensive molecular data in a very short timeframe so that it can be of the greatest use to the research, medical, and public health communities. We believe much of the proposed research should have been done two decades ago, soon after it was recognized that we had massive gaps in our knowledge about how GAS develops decreased susceptibility to beta-lactam antibiotics. Foremost, the proposed research will generate a community data resource that can be mined and used by all individuals studying GAS infections and antimicrobial resistance from different areas of emphasis.

描述性标题：对β-内酰胺抗生素易感性降低的分子基础 链球菌为链球菌 项目摘要/摘要 人类细菌病原体链球菌为链球菌（A组链球菌，气体）造成的造成更多 全球每年有7亿人感染。 β-内酰胺抗生素曾经是，而且曾经是一线 气咽炎和侵入性感染的治疗。由于仍然笼罩在神秘和 猜测，这种病原体一直统一容易受到β-内酰胺抗生素的影响，已有70年了。 但是，最近的一篇论文描述了两种引起气体感染的菌株，显着降低了 对β-内酰胺抗生素氨苄青霉素和阿莫西林的敏感性，引起了曼联的极大关注 国家和国际传染病社区。这个启示，再加上我们最近的发现 侵入性气体菌株对β-内酰胺抗生素的敏感性显着降低了 比以前认为的常见和地理广泛的广泛是 本文提出的研究。为了实现我们的目标，以极大地增强对关系的当前理解 在特定基因突变和降低气体β-内酰胺敏感性之间，以下两个特定 提出了目标。特定目标1：序列和分析> 11,000菌株的基因组以定义 青霉素结合蛋白2X（PBP2X）和青霉素结合蛋白1a中存在的突变谱 （PBP1A）从咽炎和无症状载体中回收的气体中的基因。我们将确定九个的麦克风 在2,750（25％）的菌株上常用的β-内酰胺。已知这两个基因中的突变是赋予的 许多生物（包括致病性链球菌）的β-内酰胺敏感性降低。我们将利用我们的 几十年来，从全球来源回收了40,000个气体应变的独特集合。具体目标2： 构建和分析50个等生突变菌株，以检验以下假设 PBP2X和PBP1A中的氨基酸替代降低了气体对β-内酰胺的敏感性 根据MIC敏感性分析来判断抗生素。这两个目标中提出的研究结果 将提供广泛的独特数据，以更充分地了解这个关键新的范围 抗菌抗性威胁。合理的推测结果数据也可能最终领导 为预防，限制和治疗抗生素耐药的气体感染的新型翻译策略。关键动机 是要在非常短的时间范围内生成并提供此广泛的分子数据，以便它可以是 研究，医疗和公共卫生社区的最大用途。我们相信大部分提议 研究应该是在二十年前进行的 我们对天然气如何发展的知识降低了对β-内酰胺抗生素的敏感性。最初的 拟议的研究将产生一个社区数据资源，所有个人都可以开采和使用 研究气体感染和来自不同重点区域的抗菌素耐药性。

项目成果

A Chimeric Penicillin Binding Protein 2X Significantly Decreases in Vitro Beta-Lactam Susceptibility and Increases in Vivo Fitness of Streptococcus pyogenes.

嵌合青霉素结合蛋白 2X 显着降低化脓性链球菌的体外 β-内酰胺敏感性并增加体内适应性。

• DOI: 10.1016/j.ajpath.2022.06.011
• 发表时间: 2022
• 期刊: The American journal of pathology
• 作者: Olsen,RandallJ;Zhu,Luchang;Mangham,ReganE;Faili,Ahmad;Kayal,Samer;Beres,StephenB;Musser,JamesM
• 通讯作者: Musser,JamesM