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: 10598528
• 负责人: EVGENI Veniaminovic SOKURENKO
• 金额: $ 68.93万
• 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/10598528
• 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; Probability; Proteins; Recombinants; Resistance; Resistance to infection; Structure; Time; Traveler' s diarrhea; Urinary tract infection; Uropathogen; Uropathogenic E. coli; Work; bacterial resistance; bactericide; fluoroquinolone resistance; homologous recombination; in vivo; minimal inhibitory concentration; new pandemic; 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.

抽象的 最近，氟喹诺酮类药物耐药性的大流行令人高度警惕。 被上级广泛用于治疗尿路感染，但大肠杆菌中的 FQ 耐药水平 （主要尿路病原体）FQ 目标 DNA 旋转酶 (GyrAB) 和拓扑异构酶 IV 达到 15-35%。 （ParCE），确保维持核子超螺旋和结构处于适当状态的复合物 FQ 抗性的获得主要是通过结构改变而出现的。 在所谓的喹诺酮抗性决定区 (QRDR) 中具有多个突变的靶蛋白 - 两个 GyrA 中的突变（通常是 Ser83Leu 和 Asp87Asn）与至少一种的存在紧密相关 我们发现一些临床大肠杆菌菌株更容易发生 ParC 突变（通常是 Ser80Ile）。 令人惊讶的是，这是最常见的。 大肠杆菌的泌尿道致病菌群似乎表现出对 FQ 耐药性的某些限制，可能 我们发现，由于 GyrA 和 ParC 的连续结构改变存在一些生理障碍。 相反，尿液中的 FQ 抗性分离株可以通过获得已经携带完整 FQ 的基因而出现。 一组QRDR变化，首次证明可以传输高水平的FQ电阻 例如，这就是最近的机制。 出现了新的大流行 FQ 抗性大肠杆菌克隆群 - ST1193，该群最后在全球范围内传播 在这里，我们将研究临床大肠杆菌菌株的能力之间是否存在克隆关联。 依次或通过基因转移获得并在自然界中传播全套 QRDR 突变 促进或抑制 FQ 抗性的潜在生理因素有哪些 尿路致病性大肠杆菌的出现、传播和传播。