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 抗菌耐药性最近的大流行蔓延非常令人震惊。氟喹诺酮（FQ）为 临床医生广泛用于治疗尿路感染，但大肠杆菌的FQ耐药性水平 （主要的泌尿病）达到15-35％。 FQ靶标DNA Gyrase（Gyrab）和拓扑异构酶IV （parce），确保在适合国家中维持核超级覆盖和结构的复合体 复制和分区。 FQ抗药性的主要因素通过结构性改变而出现 在所谓的奎诺酮抗性确定区域（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）与至少一个存在紧密耦合 PARC中的突变（通常是Ser80ile）。我们假设某些临床大肠杆菌菌株比 其他人要获取，也可以传播或传播FQ抗性。令人惊讶的是，最常见的 大肠杆菌的肝病群似乎证明了某些限制因素具有抗FQ，可能 由于某些物理障碍，用于沿Gyra和Parc的顺序结构改变。我们发现了 相反，通过获取已经携带完整的基因，可以出现尿FQ抗性分离株 一组QRDR变化，首次证明可以传输高级FQ电阻 在无关克隆组的临床菌株之间。例如，这是最近的机制 大肠杆菌–ST1193的新大流行FQ抗克隆群的出现，该基团在全球范围内散布 十年。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 在自然界中获取和传播QRDR突变的完整集或通过基因转移 以及促进或抑制FQ抗性的潜在生理因素 出现，传播和扩散在肝病大肠杆菌之间。