Conjugates of Ciprofloxacin and Amphiphilic Block Copoly(2-alkyl-2-oxazolines)s Overcome Efflux Pumps and Are Active against CIP-Resistant Bacteria,Molecular Pharmaceutics

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Conjugates of Ciprofloxacin and Amphiphilic Block Copoly(2-alkyl-2-oxazolines)s Overcome Efflux Pumps and Are Active against CIP-Resistant Bacteria
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-07-29 , DOI: 10.1021/acs.molpharmaceut.1c00430
Alina Romanovska ₁ , Johanna Keil ₁ , Jonas Tophoven ₁ , Murat Furkan Oruc ₁ , Martin Schmidt ₁ , Marina Breisch ₂ , Christina Sengstock ₂ , Daniela Weidlich ₃ , Dagmar Klostermeier ₃ , Joerg C Tiller ₁

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Conjugation of antibiotics with polymers is an emerging strategy to improve the performance of these important drugs. Here, the antibiotic ciprofloxacin (CIP) was conjugated with amphiphilic poly(2-oxazoline) (POx) block copolymers to investigate whether the activity of the antibiotic was enhanced due to additionally induced membrane activity. The resulting polymer–antibiotic conjugates (PACs) are an order of magnitude more active against the bacterial strain Staphylococcus aureus than CIP and show high activities against numerous pathogenic bacterial strains. Their high activity depends on an optimal hydrophobic/hydrophilic balance (HHB) of the POx tail. Mechanistic studies revealed that the derivatization of CIP required for the polymer conjugation lowers the affinity of the antibiotic to its target topoisomerase IV. However, the amphiphilic PACs are most likely concentrated within the bacterial cytoplasm, which overcompensates the loss of affinity and results in high antibacterial activity. In addition, the development of resistance in S. aureus and Escherichia coli is slowed down. More importantly, the amphiphilic PACs are active against CIP-resistant S. aureus and E. coli. The PACs with the highest activity are not cytotoxic toward human stem cells and do not lyse blood cells in saturated solution.

中文翻译：

环丙沙星和两亲嵌段共聚 (2-烷基-2-恶唑啉) 的偶联物克服了外排泵问题，并对 CIP 抗性细菌具有活性

抗生素与聚合物的结合是提高这些重要药物性能的新兴策略。在这里，抗生素环丙沙星 (CIP) 与两亲性聚 (2-恶唑啉) (POx) 嵌段共聚物共轭，以研究抗生素的活性是否由于额外诱导的膜活性而增强。所得聚合物-抗生素缀合物 (PAC) 对金黄色葡萄球菌菌株的活性要高一个数量级与 CIP 相比，对多种致病菌株表现出高活性。它们的高活性取决于 POx 尾部的最佳疏水/亲水平衡 (HHB)。机理研究表明，聚合物缀合所需的 CIP 衍生化降低了抗生素对其目标拓扑异构酶 IV 的亲和力。然而，两亲性 PAC 最有可能集中在细菌细胞质内，这会过度补偿亲和力的损失并导致高抗菌活性。此外，金黄色葡萄球菌和大肠杆菌的耐药性发展也减慢了。更重要的是，两亲性 PAC 对 CIP 抗性金黄色葡萄球菌和大肠杆菌具有活性. 具有最高活性的 PAC 对人类干细胞没有细胞毒性，并且不会在饱和溶液中溶解血细胞。

更新日期：2021-09-06

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