新型拓扑异构酶抑制剂：评估氟喹诺酮耐药大肠杆菌中 gepotidacin 和 zoliflodacin 的效价在失活时的差异，并区分它们的外排泵底物性质。
New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon Inactivation and Differentiating Their Efflux Pump Substrate Nature.
机构信息
Division of Infectious Diseases, Department of Medicine II, University Hospital and Medical Center, Freiburg, Germany
Division of Infectious Diseases, Department of Medicine II, University Hospital and Medical Center, Freiburg, Germany.
出版信息
Antimicrob Agents Chemother. 2021 Jan 20;65(2). doi: 10.1128/AAC.01803-20.
Abstract
Inactivating in multidrug-resistant with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the selectivity of RND (resistance-nodulation-cell division)-type transporters, efflux inhibitors, and AcrB porter domain mutations were demonstrated. The findings should reinforce efforts to develop efflux-bypassing drugs and provide AcrB targets with critical relevance for this purpose.
摘要
在具有不同序列类型和喹诺酮类药物耐药决定突变的多重耐药中，失活揭示了一流拓扑异构酶抑制剂 gepotidacin 和 zoliflodacin 的显著增强活性。与氟喹诺酮类药物相比，这两种结构上无关的化合物在 RND（耐药-结节-细胞分裂）型转运蛋白、外排抑制剂和 AcrB porter 结构域突变的选择性方面存在差异。这些发现应该加强开发外排旁路药物的努力，并为这一目的提供与 AcrB 靶标密切相关的靶点。
相似文献
1
New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon Inactivation and Differentiating Their Efflux Pump Substrate Nature.新型拓扑异构酶抑制剂：评估氟喹诺酮耐药大肠杆菌中 gepotidacin 和 zoliflodacin 的效价在失活时的差异，并区分它们的外排泵底物性质。
Antimicrob Agents Chemother. 2021 Jan 20;65(2). doi: 10.1128/AAC.01803-20.
2
Altered spectrum of multidrug resistance associated with a single point mutation in the Escherichia coli RND-type MDR efflux pump YhiV (MdtF).与大肠杆菌RND型多药耐药外排泵YhiV（MdtF）中的单点突变相关的多药耐药谱改变。
J Antimicrob Chemother. 2007 Jun;59(6):1216-22. doi: 10.1093/jac/dkl426. Epub 2006 Oct 24.
3
Expression of multidrug efflux pump genes acrAB-tolC, mdfA, and norE in Escherichia coli clinical isolates as a function of fluoroquinolone and multidrug resistance.多药外排泵基因 acrAB-tolC、mdfA 和 norE 在氟喹诺酮类和多药耐药大肠杆菌临床分离株中的表达。
Antimicrob Agents Chemother. 2011 Feb;55(2):921-4. doi: 10.1128/AAC.00996-10. Epub 2010 Nov 22.
4
Chlorpromazine and Amitriptyline Are Substrates and Inhibitors of the AcrB Multidrug Efflux Pump.氯丙嗪和阿米替林是 AcrB 多药外排泵的底物和抑制剂。
mBio. 2020 Jun 2;11(3):e00465-20. doi: 10.1128/mBio.00465-20.
5
Efflux-Mediated Resistance to New Oxazolidinones and Pleuromutilin Derivatives in Escherichia coli with Class Specificities in the Resistance-Nodulation-Cell Division-Type Drug Transport Pathways.耐药-结节-分裂型药物转运途径中，具有特定类别的大肠杆菌对新型恶唑烷酮类和截短侧耳素衍生物的外排介导的耐药性。
Antimicrob Agents Chemother. 2019 Aug 23;63(9). doi: 10.1128/AAC.01041-19. Print 2019 Sep.
6
Exploring the contribution of efflux on the resistance to fluoroquinolones in clinical isolates of Escherichia coli.探讨外排泵对临床分离大肠杆菌耐氟喹诺酮类药物的作用。
Microb Drug Resist. 2013 Dec;19(6):469-76. doi: 10.1089/mdr.2013.0058. Epub 2013 Aug 2.
7
Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives.新型强效吡喃并吡啶衍生物抑制AcrB多药外排泵的分子基础
Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3509-14. doi: 10.1073/pnas.1602472113. Epub 2016 Mar 14.
8
Exploring the Contribution of the AcrB Homolog MdtF to Drug Resistance and Dye Efflux in a Multidrug Resistant Isolate.探究AcrB同源物MdtF对多重耐药菌株耐药性及染料外排的作用
Antibiotics (Basel). 2021 Apr 28;10(5):503. doi: 10.3390/antibiotics10050503.
9
Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4-ST131-H30R and O1-ST648.替加环素不敏感性仅在耐氟喹诺酮的大肠埃希菌临床分离株中出现，包括主要的多重耐药谱系O25b:H4-ST131-H30R和O1-ST648。
Antimicrob Agents Chemother. 2017 Jan 24;61(2). doi: 10.1128/AAC.01654-16. Print 2017 Feb.
10
Evidence of a Substrate-Discriminating Entrance Channel in the Lower Porter Domain of the Multidrug Resistance Efflux Pump AcrB.多药耐药外排泵AcrB下转运结构域中底物区分入口通道的证据。
Antimicrob Agents Chemother. 2016 Jun 20;60(7):4315-23. doi: 10.1128/AAC.00314-16. Print 2016 Jul.
引用本文的文献
1
Management and prevention of Neisseria meningitidis and Neisseria gonorrhoeae infections in the context of evolving antimicrobial resistance trends.在不断演变的抗菌药物耐药性趋势背景下，脑膜炎奈瑟菌和淋病奈瑟菌感染的管理与预防
Eur J Clin Microbiol Infect Dis. 2025 Feb;44(2):233-250. doi: 10.1007/s10096-024-04968-8. Epub 2024 Nov 27.
2
Comparative reassessment of AcrB efflux inhibitors reveals differential impact of specific pump mutations on the activity of potent compounds.比较评估 AcrB 外排泵抑制剂揭示了特定泵突变对强效化合物活性的影响差异。
Microbiol Spectr. 2024 Feb 6;12(2):e0304523. doi: 10.1128/spectrum.03045-23. Epub 2024 Jan 3.
3
All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches.条条大路通罗马：采用不同的药代动力学/药效学建模方法提高目标达成的概率。
Antibiotics (Basel). 2023 Apr 1;12(4):690. doi: 10.3390/antibiotics12040690.
4
Stimulating Transcription in Antibiotic-Tolerant Escherichia coli Sensitizes It to Fluoroquinolone and Nonfluoroquinolone Topoisomerase Inhibitors.抗生素耐受型大肠杆菌中转录的刺激使其对氟喹诺酮类和非氟喹诺酮类拓扑异构酶抑制剂敏感。
Antimicrob Agents Chemother. 2023 Apr 18;67(4):e0163922. doi: 10.1128/aac.01639-22. Epub 2023 Mar 23.
5
Effects of TolC on the pathogenicity of porcine extraintestinal pathogenic .托尔克氏菌外膜蛋白 TolC 对猪致病性的影响
Front Immunol. 2022 Aug 18;13:929740. doi: 10.3389/fimmu.2022.929740. eCollection 2022.
6
Metallo-β-Lactamase Inhibitor Phosphonamidate Monoesters.金属β-内酰胺酶抑制剂膦酰胺单酯
ACS Omega. 2022 Jan 25;7(5):4550-4562. doi: 10.1021/acsomega.1c06527. eCollection 2022 Feb 8.
7
Exploring the Contribution of the AcrB Homolog MdtF to Drug Resistance and Dye Efflux in a Multidrug Resistant Isolate.探究AcrB同源物MdtF对多重耐药菌株耐药性及染料外排的作用
Antibiotics (Basel). 2021 Apr 28;10(5):503. doi: 10.3390/antibiotics10050503.
本文引用的文献
1
Efflux-Mediated Resistance to New Oxazolidinones and Pleuromutilin Derivatives in Escherichia coli with Class Specificities in the Resistance-Nodulation-Cell Division-Type Drug Transport Pathways.耐药-结节-分裂型药物转运途径中，具有特定类别的大肠杆菌对新型恶唑烷酮类和截短侧耳素衍生物的外排介导的耐药性。
Antimicrob Agents Chemother. 2019 Aug 23;63(9). doi: 10.1128/AAC.01041-19. Print 2019 Sep.
2
Quantitative contribution of efflux to multi-drug resistance of clinical Escherichia coli and Pseudomonas aeruginosa strains.临床型大肠埃希菌和铜绿假单胞菌多重耐药中外排泵作用的定量贡献。
EBioMedicine. 2019 Mar;41:479-487. doi: 10.1016/j.ebiom.2019.02.061. Epub 2019 Mar 7.
3
Proof of an Outer Membrane Target of the Efflux Inhibitor Phe-Arg-β-Naphthylamide from Random Mutagenesis.随机诱变证明外膜泵抑制剂苯丙氨酸-精氨酸-β-萘酰胺的靶标。
Molecules. 2019 Jan 29;24(3):470. doi: 10.3390/molecules24030470.
4
In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae.新型三氮杂吖庚因类药物 gepotidacin（GSK2140944）对耐多药淋病奈瑟菌的体外活性。
J Antimicrob Chemother. 2018 Aug 1;73(8):2072-2077. doi: 10.1093/jac/dky162.
5
Molecular Properties That Define the Activities of Antibiotics in Escherichia coli and Pseudomonas aeruginosa.定义抗生素在大肠杆菌和铜绿假单胞菌中活性的分子特性。
ACS Infect Dis. 2018 Aug 10;4(8):1223-1234. doi: 10.1021/acsinfecdis.8b00036. Epub 2018 May 25.
6
Contribution of AcrAB-TolC to multidrug resistance in an Escherichia coli sequence type 131 isolate.一株大肠杆菌 131 型分离株中 AcrAB-TolC 对多药耐药的贡献。
Int J Antimicrob Agents. 2017 Sep;50(3):477-481. doi: 10.1016/j.ijantimicag.2017.03.023. Epub 2017 Jul 6.
7
Gepotidacin (GSK2140944) Activity against Gram-Positive and Gram-Negative Bacteria.格帕沙星（GSK2140944）对革兰氏阳性菌和革兰氏阴性菌的活性。
Antimicrob Agents Chemother. 2017 Jun 27;61(7). doi: 10.1128/AAC.00468-17. Print 2017 Jul.
8
Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae.格帕沙星（GSK2140944）对淋病奈瑟菌的活性。
Antimicrob Agents Chemother. 2017 Feb 23;61(3). doi: 10.1128/AAC.02047-16. Print 2017 Mar.
9
Evidence of a Substrate-Discriminating Entrance Channel in the Lower Porter Domain of the Multidrug Resistance Efflux Pump AcrB.多药耐药外排泵AcrB下转运结构域中底物区分入口通道的证据。
Antimicrob Agents Chemother. 2016 Jun 20;60(7):4315-23. doi: 10.1128/AAC.00314-16. Print 2016 Jul.
10
Novel Piperazine Arylideneimidazolones Inhibit the AcrAB-TolC Pump in Escherichia coli and Simultaneously Act as Fluorescent Membrane Probes in a Combined Real-Time Influx and Efflux Assay.新型哌嗪亚芳基咪唑啉酮可抑制大肠杆菌中的AcrAB-TolC泵，并在实时流入和流出联合测定中同时充当荧光膜探针。
Antimicrob Agents Chemother. 2016 Mar 25;60(4):1974-83. doi: 10.1128/AAC.01995-15. Print 2016 Apr.
Zotero 插件