Chonnikan Hanpaibool, Puey Ounjai, Sirilata Yotphan, Adrian J. Mulholland, James Spencer, Natharin Ngamwongsatit, Thanyada Rungrotmongkol
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Our preliminary results showed that treatment with a reference pyrazolone compound significantly reduced colistin minimal inhibitory concentrations in <i>Escherichia coli</i> expressing <i>mcr-1</i> mediated colistin resistance (Hanpaibool et al. in ACS Omega, 2023). A docking-MD combination was used in an ensemble-based docking approach to identify further pyrazolone compounds as candidate MCR-1 inhibitors. Docking simulations revealed that 13/28 of the pyrazolone compounds tested are predicted to have lower binding free energies than the reference compound. Four of these were chosen for in vitro testing, with the results demonstrating that all the compounds tested could lower colistin MICs in an <i>E. coli</i> strain carrying the <i>mcr-1</i> gene. Docking of pyrazolones into the MCR-1 active site reveals residues that are implicated in ligand–protein interactions, particularly E246, T285, H395, H466, and H478, which are located in the MCR-1 active site and which participate in interactions with MCR-1 in ≥ 8/10 of the lowest energy complexes. This study establishes pyrazolone-induced colistin susceptibility in <i>E</i>. <i>coli</i> carrying the <i>mcr-1</i> gene, providing a method for the development of novel treatments against colistin-resistant bacteria.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 10","pages":"479 - 489"},"PeriodicalIF":3.0000,"publicationDate":"2023-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Enhancement by pyrazolones of colistin efficacy against mcr-1-expressing E. coli: an in silico and in vitro investigation\",\"authors\":\"Chonnikan Hanpaibool, Puey Ounjai, Sirilata Yotphan, Adrian J. 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Our preliminary results showed that treatment with a reference pyrazolone compound significantly reduced colistin minimal inhibitory concentrations in <i>Escherichia coli</i> expressing <i>mcr-1</i> mediated colistin resistance (Hanpaibool et al. in ACS Omega, 2023). A docking-MD combination was used in an ensemble-based docking approach to identify further pyrazolone compounds as candidate MCR-1 inhibitors. Docking simulations revealed that 13/28 of the pyrazolone compounds tested are predicted to have lower binding free energies than the reference compound. Four of these were chosen for in vitro testing, with the results demonstrating that all the compounds tested could lower colistin MICs in an <i>E. coli</i> strain carrying the <i>mcr-1</i> gene. 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引用次数: 0
摘要
由于抗生素耐药性的出现,多粘菌素最近已恢复用于治疗急性多重耐药革兰氏阴性细菌感染。带正电的粘菌素与带负电的脂质结合,破坏革兰氏阴性菌的外膜。然而,由移动粘菌素抗性(mcr)基因编码的mcr -1蛋白通过催化磷酸乙醇胺(PEA)转移到脂质A上,中和其负电荷,从而减少其与粘菌素的相互作用,参与细菌对粘菌素的抗性。我们的初步结果显示,用吡唑酮类参考化合物处理可显著降低表达mcr-1介导的粘菌素耐药性的大肠杆菌中粘菌素的最低抑制浓度(Hanpaibool et al. in ACS Omega, 2023)。在基于集成的对接方法中,使用对接- md组合来鉴定进一步的吡唑酮化合物作为候选MCR-1抑制剂。对接模拟结果表明,13/28的吡唑酮类化合物的结合自由能比参考化合物低。选择其中的四种进行体外测试,结果表明,所有测试的化合物都可以降低携带mcr-1基因的大肠杆菌菌株中的粘菌素mic。吡唑酮类化合物与MCR-1活性位点对接,揭示了与配体-蛋白相互作用有关的残基,特别是位于MCR-1活性位点的E246、T285、H395、H466和H478,它们在≥8/10的最低能量配合物中与MCR-1相互作用。本研究在携带mcr-1基因的大肠杆菌中建立了吡唑啉酮诱导的粘菌素敏感性,为开发新的治疗粘菌素耐药菌的方法提供了方法。
Enhancement by pyrazolones of colistin efficacy against mcr-1-expressing E. coli: an in silico and in vitro investigation
Owing to the emergence of antibiotic resistance, the polymyxin colistin has been recently revived to treat acute, multidrug-resistant Gram-negative bacterial infections. Positively charged colistin binds to negatively charged lipids and damages the outer membrane of Gram-negative bacteria. However, the MCR-1 protein, encoded by the mobile colistin resistance (mcr) gene, is involved in bacterial colistin resistance by catalysing phosphoethanolamine (PEA) transfer onto lipid A, neutralising its negative charge, and thereby reducing its interaction with colistin. Our preliminary results showed that treatment with a reference pyrazolone compound significantly reduced colistin minimal inhibitory concentrations in Escherichia coli expressing mcr-1 mediated colistin resistance (Hanpaibool et al. in ACS Omega, 2023). A docking-MD combination was used in an ensemble-based docking approach to identify further pyrazolone compounds as candidate MCR-1 inhibitors. Docking simulations revealed that 13/28 of the pyrazolone compounds tested are predicted to have lower binding free energies than the reference compound. Four of these were chosen for in vitro testing, with the results demonstrating that all the compounds tested could lower colistin MICs in an E. coli strain carrying the mcr-1 gene. Docking of pyrazolones into the MCR-1 active site reveals residues that are implicated in ligand–protein interactions, particularly E246, T285, H395, H466, and H478, which are located in the MCR-1 active site and which participate in interactions with MCR-1 in ≥ 8/10 of the lowest energy complexes. This study establishes pyrazolone-induced colistin susceptibility in E. coli carrying the mcr-1 gene, providing a method for the development of novel treatments against colistin-resistant bacteria.
期刊介绍:
The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas:
- theoretical chemistry;
- computational chemistry;
- computer and molecular graphics;
- molecular modeling;
- protein engineering;
- drug design;
- expert systems;
- general structure-property relationships;
- molecular dynamics;
- chemical database development and usage.