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Insights into the Kinetics of the Resistance Formation of Bacteria against Ciprofloxacin Poly(2-methyl-2-oxazoline) Conjugates
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-06-21 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00361 Martin Schmidt , Alina Romanovska , Youssef Wolf , Thanh-Duong Nguyen , Anna Krupp , Hannah L. Tumbrink 1 , Jonas Lategahn 1 , Jan Volmer , Daniel Rauh 1 , Stephan Luetz , Christian Krumm , Joerg C. Tiller
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-06-21 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00361 Martin Schmidt , Alina Romanovska , Youssef Wolf , Thanh-Duong Nguyen , Anna Krupp , Hannah L. Tumbrink 1 , Jonas Lategahn 1 , Jan Volmer , Daniel Rauh 1 , Stephan Luetz , Christian Krumm , Joerg C. Tiller
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The influence on the resistance formation of polymers attached to antibiotics has rarely been investigated. In this study, ciprofloxacin (CIP) was conjugated to poly(2-methyl-2-oxazoline)s with an ethylene diamine end group (Me-PMOx28-EDA) via two different spacers (CIP modified with α,α′-dichloro-p-xylene—xCIP, CIP modified with chloroacetyl chloride—eCIP). The antibacterial activity of the conjugates against a number of bacterial strains shows a great dependence on the nature of the spacer. The Me-PMOx39-EDA-eCIP, containing a potentially cleavable linker, does not exhibit a molecular weight dependence on antibacterial activity in contrast to Me-PMOx27-EDA-xCIP. The resistance formation of both conjugates against Staphylococcus aureus and Escherichia coli was investigated. Both conjugates showed the potential to significantly delay the formation of resistant bacteria compared to the unmodified CIP. Closer inspection of a possible resistance mechanism by genome sequencing of the topoisomerase IV region of resistant S. aureus revealed that this bacterium mutates at the same position when building up resistance to CIP and to Me-PMOx27-EDA-xCIP. However, the S. aureus cells that became resistant against the polymer conjugate are fully susceptible to CIP. Thus, conjugation of CIP with PMOx seems to alter the resistance mechanism.
中文翻译：
细菌对环丙沙星聚（2-甲基-2-恶唑啉）缀合物的抗性形成动力学的见解。
很少研究对附着在抗生素上的聚合物的耐药性形成的影响。在这项研究中，环丙沙星（CIP）通过两个不同的间隔基（用α，α'-二氯修饰的CIP ）与带有乙二胺端基（Me-PMOx 28 -EDA）的聚（2-甲基-2-恶唑啉）共轭-对二甲苯-xCIP，经氯乙酰氯修饰的CIP-eCIP）。缀合物对许多细菌菌株的抗菌活性显示出对间隔基的性质的极大依赖性。在ME-PMOx 39 -EDA-ECIP，含有潜在切割的接头，没有表现出对在对比ME-PMOx抗菌活性的分子量依赖性27 -EDA-xCIP。两种结合物对抗性的形成研究了金黄色葡萄球菌和大肠杆菌。与未修饰的CIP相比，两种结合物均显示出显着延迟耐药菌形成的潜力。通过对抗性金黄色葡萄球菌的拓扑异构酶IV区进行基因组测序，仔细检查可能的抗性机制，发现该细菌在建立对CIP和Me-PMOx 27 -EDA-xCIP的抗性时会在同一位置突变。然而，变得对聚合物缀合物具有抗性的金黄色葡萄球菌细胞对CIP完全敏感。因此，CIP与PMOx的结合似乎改变了耐药机制。
更新日期：2018-06-21
中文翻译：
细菌对环丙沙星聚（2-甲基-2-恶唑啉）缀合物的抗性形成动力学的见解。
很少研究对附着在抗生素上的聚合物的耐药性形成的影响。在这项研究中，环丙沙星（CIP）通过两个不同的间隔基（用α，α'-二氯修饰的CIP ）与带有乙二胺端基（Me-PMOx 28 -EDA）的聚（2-甲基-2-恶唑啉）共轭-对二甲苯-xCIP，经氯乙酰氯修饰的CIP-eCIP）。缀合物对许多细菌菌株的抗菌活性显示出对间隔基的性质的极大依赖性。在ME-PMOx 39 -EDA-ECIP，含有潜在切割的接头，没有表现出对在对比ME-PMOx抗菌活性的分子量依赖性27 -EDA-xCIP。两种结合物对抗性的形成研究了金黄色葡萄球菌和大肠杆菌。与未修饰的CIP相比，两种结合物均显示出显着延迟耐药菌形成的潜力。通过对抗性金黄色葡萄球菌的拓扑异构酶IV区进行基因组测序，仔细检查可能的抗性机制，发现该细菌在建立对CIP和Me-PMOx 27 -EDA-xCIP的抗性时会在同一位置突变。然而，变得对聚合物缀合物具有抗性的金黄色葡萄球菌细胞对CIP完全敏感。因此，CIP与PMOx的结合似乎改变了耐药机制。
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