Pyrazolones Potentiate Colistin Activity against MCR-1-Producing Resistant Bacteria: Computational and Microbiological Study.
Pyrazolones Potentiate Colistin Activity against MCR-1-Producing Resistant Bacteria: Computational and Microbiological Study.
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DOI：
10.1021/acsomega.2c07165
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发表时间：
2023-03-07
期刊：
影响因子：
4.1
通讯作者：
Rungrotmongkol, Thanyada
中科院分区：
文献类型：
--
作者：
Hanpaibool, Chonnikan;Ngamwongsatit, Natharin;Ounjai, Puey;Yotphan, Sirilata;Wolschann, Peter;Mulholland, Adrian J.;Spencer, James;Rungrotmongkol, Thanyada
多粘菌素是广泛耐药革兰氏阴性菌的最后一种抗生素。粘菌素与脂质A结合破坏革兰氏阴性菌外膜，但移动的粘菌素抗性（mcr）基因家族成员通过催化磷酸乙醇胺（PEA）转移到脂质A上，中和其负电荷以减少粘菌素相互作用来赋予抗性。已在临床和环境分离株中鉴定出多种mcr亚型，其中mcr-1分布最广，mcr-3在南亚和东亚常见。初步筛选显示，吡唑啉酮类药物治疗可显著降低mcr-1介导的粘菌素耐药性，但对mcr-3无影响。分子动力学（MD）模拟的催化结构域的MCR-1和MCR-3的同源模型，在不同的质子化状态的活性位点残基H395/H380和H478/H463，表明MCR-1的活性位点具有更大的水的可及性比MCR-3，但这是受质子化的变化。利用分子动力学优化的MCR-1和MCR-3结构对20个吡唑啉酮衍生物进行了虚拟筛选。将其对接至MCR-1/MCR-3活性位点，可识别可能参与蛋白质-配体相互作用的常见残基，特别是PEA添加的催化性苏氨酸（MCR-1 T285、MCR-3 T277）位点，以及与相邻氨基酸的差异性相互作用。最小抑菌浓度试验表明，具有最低预测结合能（ST 3f）的吡唑酮可恢复表达mcr-1的大肠杆菌对粘菌素的敏感性，但不能恢复mcr-3的敏感性。因此，模拟表明MCR-1和MCR-3之间活性位点结构的差异可能导致吡唑啉酮结合的差异，因此与对生产者E的差异效应有关。杆菌这项工作确定了吡唑啉酮能够恢复产mcr-1细菌的粘菌素敏感性，为进一步研究其作为磷酸乙醇胺转移酶抑制剂的活性以及其对mcr亚型的差异活性奠定了基础。
The polymyxin colistin is a last line antibiotic for extensively resistant Gram-negative bacteria. Colistin binding to lipid A disrupts the Gram-negative outer membrane, but mobile colistin resistance (mcr) gene family members confer resistance by catalyzing phosphoethanolamine (PEA) transfer onto lipid A, neutralizing its negative charge to reduce colistin interactions. Multiple mcr isoforms have been identified in clinical and environmental isolates, with mcr-1 being the most widespread and mcr-3 being common in South and East Asia. Preliminary screening revealed that treatment with pyrazolones significantly reduced mcr-1, but not mcr-3, mediated colistin resistance. Molecular dynamics (MD) simulations of the catalytic domains of MCR-1 and a homology model of MCR-3, in different protonation states of active site residues H395/H380 and H478/H463, indicate that the MCR-1 active site has greater water accessibility than MCR-3, but that this is less influenced by changes in protonation. MD-optimized structures of MCR-1 and MCR-3 were used in virtual screening of 20 pyrazolone derivatives. Docking of these into the MCR-1/MCR-3 active sites identifies common residues likely to be involved in protein–ligand interactions, specifically the catalytic threonine (MCR-1 T285, MCR-3 T277) site of PEA addition, as well as differential interactions with adjacent amino acids. Minimal inhibitory concentration assays showed that the pyrazolone with the lowest predicted binding energy (ST3f) restores colistin susceptibility of mcr-1, but not mcr-3, expressing Escherichia coli. Thus, simulations indicate differences in the active site structure between MCR-1 and MCR-3 that may give rise to differences in pyrazolone binding and so relate to differential effects upon producer E. coli. This work identifies pyrazolones as able to restore colistin susceptibility of mcr-1-producing bacteria, laying the foundation for further investigations of their activity as phosphoethanolamine transferase inhibitors as well as of their differential activity toward mcr isoforms.
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影响因子：
4.5
作者：
Andrade FF;Silva D;Rodrigues A;Pina-Vaz C
通讯作者：
Pina-Vaz C
影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
DOI：
10.1107/s2053230x17009669
发表时间：
2017-08-01
期刊：
Acta crystallographica. Section F, Structural biology communications
影响因子：
--
作者：
Coates K;Walsh TR;Spencer J;Hinchliffe P
通讯作者：
Hinchliffe P
影响因子：
4.6
作者：
Iramiot, Jacob Stanley;Kajumbula, Henry;Asiimwe, Benon B.
通讯作者：
Asiimwe, Benon B.
影响因子：
3.8
作者：
de los Santos, Eliana;Lavina, Magela;Poey, Maria Eloisa
通讯作者：
Poey, Maria Eloisa