Mechanism of the Fluoroquinolone Resistance Acquisition in Enterobacteria

肠杆菌对氟喹诺酮类耐药的获得机制

• 批准号: 10383691
• 负责人: EVGENI Veniaminovic SOKURENKO
• 金额: $ 73.12万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383691
• 关键词: Affect; Antibiotic Resistance; Antimicrobial Resistance; Bacterial Chromosomes; Bioinformatics; Chromosomes; Ciprofloxacin; Clinical; Code; Communities; Complex; Coupled; DNA; DNA Gyrase; DNA Topoisomerase IV; Development; Distant; Ensure; Enterobacteriaceae; Escherichia coli; Event; Evolution; Fluoroquinolones; Gene Transfer; Genes; Genetic Recombination; Horizontal Gene Transfer; Hospitals; In Vitro; Infection; Length; Maintenance; Medicine; Molecular; Molecular Evolution; Multi-Drug Resistance; Mutation; Nature; Physiological; Plasmids; Positioning Attribute; Proteins; Recombinants; Resistance; Resistance to infection; Structure; Time; Traveler' s diarrhea; Urinary tract infection; Uropathogen; Uropathogenic E. coli; Work; bacterial resistance; bactericide; emerging antimicrobial resistance; fluoroquinolone resistance; homologous recombination; in vivo; minimal inhibitory concentration; pandemic disease; pathogen; progenitor; quinolone resistance; restraint; success; transmission process; urinary

ABSTRACT Recent pandemic spread of antimicrobial resistance is highly alarming. Fluoroquinolones (FQ) are broadly used by clinicians for treatment of urinary tract infections, but FQ resistance levels in Escherichia coli (the main uropathogen) are reaching 15-35%. FQ targets DNA gyrase (GyrAB) and topoisomerase IV (ParCE), complexes that ensure maintenance of nucleoid super-coiling and structure in states appropriate for replication and partitioning. The FQ resistance acquisition primarily emerges by structural alteration of the target proteins with multiple mutations in so-called quinolone-resistance determining regions (QRDR) - two mutations in GyrA (usually Ser83Leu and Asp87Asn) that are tightly coupled to the presence of at least one mutation in ParC (usually Ser80Ile). We hypothesize that some clinical E. coli strains are more prone than others to acquire and, also, to spread or transmit the FQ resistance. Surprisingly, the most common uropathogenic groups of E. coli appear to demonstrate certain restraints to becoming FQ resistant, probably due to some physiological barriers for the sequential structural alteration of GyrA and ParC. We discovered that, instead, that urinary FQ resistant isolates can emerge by acquisition of genes already carrying the full set of QRDR changes, demonstrating for the first time that high-level FQ resistance can be transmitted between clinical strains of unrelated clonal groups. This, for example, was the mechanism of recent emergence of new pandemic FQ resistant clonal group of E. coli – ST1193 that spread globally with last decade. Here we will study whether there is a clonal association between the ability of clinical E. coli strains to acquire and spread in nature the full set of QRDR mutations sequentially or, alternatively, by gene transfer and what could be potential physiological factors that either promote or restrain the FQ resistance emergence, transmission and spread among uropathogenic E. coli.

摘要 最近抗菌素耐药性的大流行蔓延令人高度震惊。氟喹诺酮类（FQ）是 临床医生广泛用于治疗尿路感染，但大肠杆菌中的FQ耐药水平 (the主要泌尿系病原体）达到15- 35%。FQ靶向DNA促旋酶（GyrAB）和拓扑异构酶IV （ParCE），确保维持类核超螺旋和结构处于适合于 复制和分区。FQ抗性的获得主要是通过结构改变而出现的。 在所谓的喹诺酮耐药决定区（QRDR）中具有多个突变的靶蛋白-两个 GyrA中的突变（通常是Ser 83 Leu和Asp 87 Asn），这些突变与至少一个 ParC突变（通常为Ser 80 Ile）。我们假设一些临床E.大肠杆菌菌株比 其他人获得，也传播或传播FQ抗性。令人惊讶的是，最常见的 泌尿系致病群E.大肠杆菌似乎表现出一定的限制，成为FQ耐药，可能 这是由于GyrA和ParC的连续结构改变存在一些生理障碍。我们发现 相反，尿FQ耐药分离株可以通过获得已经携带完整的 一组QRDR变化，首次证明高水平的FQ电阻可以传输 在不相关的克隆群的临床菌株之间。例如，这就是最近的机制， 新的大流行性抗FQ克隆群的出现。大肠杆菌-ST 1193， 十年在此，我们将研究临床大肠杆菌的能力之间是否存在克隆关联。杆菌菌株 在自然界中顺序地或替代地通过基因转移获得和传播全套QRDR突变 哪些潜在的生理因素可能促进或抑制FQ抗性 泌尿系致病性E.杆菌