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： β-内酰胺类抗生素敏感性降低的分子基础 化脓性链球菌 项目摘要/总结 人类细菌病原体化脓性链球菌（A 族链球菌，GAS）可引起超过 全球每年有 7 亿人感染。 β-内酰胺抗生素现在是并且一直是一线抗生素 治疗 GAS 咽炎和侵袭性感染。由于仍然笼罩在神秘之中的原因 据推测，这种病原体在 70 年来一直对 β-内酰胺抗生素敏感。 然而，最近的一篇论文描述了两种引起 GAS 感染的菌株，其感染率显着下降。 对β-内酰胺类抗生素氨苄青霉素和阿莫西林的敏感性引起了美国的高度关注 各国和国际传染病界。这一启示，加上我们最近的发现 对 β-内酰胺抗生素敏感性显着降低的侵袭性 GAS 菌株要多得多 普遍性和地理分布比以前想象的更广泛，成为了 本文提出的研究。实现大幅增进当前对两国关系的了解的目标 在特定基因突变和 GAS β-内酰胺敏感性降低之间，以下两个特定的 提出了目标。具体目标 1：对超过 11,000 个菌株的基因组进行测序和分析，以确定 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 从咽炎和无症状携带者中恢复的 GAS 中的 (pbp1A) 基因。我们将确定 9 个国家的 MIC 2,750 种 (25%) 菌株中常用 β-内酰胺。已知这两个基因的突变会导致 降低许多生物体（包括致病性链球菌）的 β-内酰胺敏感性。我们将利用我们的 数十年来从全球来源恢复的 40,000 个 GAS 菌株的独特集合。具体目标2： 构建并分析 50 个同基因突变株，以检验特定天然存在的假设 PBP2X 和 PBP1A 中的氨基酸替代降低了 GAS 对 β-内酰胺的敏感性 抗生素，根据MIC药敏分析判断。这两个目标提出的研究结果 将提供广泛的独特数据，以更全面地了解这一关键新产品的范围 抗菌素耐药性威胁。有理由推测，由此产生的数据也可能最终导致 预防、限制和治疗抗生素耐药性 GAS 感染的新转化策略。一个关键动机 是在很短的时间内生成并提供这些广泛的分子数据，以便它能够 对研究、医疗和公共卫生界的最大用途。我们相信大部分提议 研究本应在二十年前就应该进行，当时我们已经认识到我们在这方面存在巨大差距。 我们了解 GAS 如何降低对 β-内酰胺抗生素的敏感性。最重要的是， 拟议的研究将生成可供所有人挖掘和使用的社区数据资源 从不同的重点领域研究 GAS 感染和抗菌药物耐药性。

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。

• 发表时间: 2022-10
• 作者: Olsen, Randall J;Zhu, Luchang;Mangham, Regan E;Faili, Ahmad;Kayal, Samer;Beres, Stephen B;Musser, James M
• 通讯作者: Musser, James M