Shavit Michal, Pokrovskaya Varvara, Belakhov Valery, Baasov Timor
The Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion - Israel Institute of Technology, Haifa 3200003, Israel.
The Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion - Israel Institute of Technology, Haifa 3200003, Israel.
Bioorg Med Chem. 2017 Jun 1;25(11):2917-2925. doi: 10.1016/j.bmc.2017.02.068. Epub 2017 Mar 16.
To address the growing problem of antibiotic resistance, a set of 12 hybrid compounds that covalently link fluoroquinolone (ciprofloxacin) and aminoglycoside (kanamycin A) antibiotics were synthesized, and their activity was determined against both Gram-negative and Gram-positive bacteria, including resistant strains. The hybrids were antagonistic relative to the ciprofloxacin, but were substantially more potent than the parent kanamycin against Gram-negative bacteria, and overcame most dominant resistance mechanisms to aminoglycosides. Selected hybrids were 42-640 fold poorer inhibitors of bacterial protein synthesis than the parent kanamycin, while they displayed similar inhibitory activity to that of ciprofloxacin against DNA gyrase and topoisomerase IV enzymes. The hybrids showed significant delay of resistance development in both E. coli and B. subtilis in comparison to that of component drugs alone or their 1:1 mixture. More generally, the data suggest that an antagonistic combination of aminoglycoside-fluoroquinolone hybrids can lead to new compounds that slowdown/prevent the emergence of resistance.
为解决日益严重的抗生素耐药性问题，合成了一组12种将氟喹诺酮（环丙沙星）和氨基糖苷类（卡那霉素A）抗生素共价连接的杂合化合物，并测定了它们对革兰氏阴性菌和革兰氏阳性菌（包括耐药菌株）的活性。这些杂合体相对于环丙沙星具有拮抗作用，但对革兰氏阴性菌的效力明显高于亲本卡那霉素，并且克服了对氨基糖苷类的大多数主要耐药机制。所选杂合体对细菌蛋白质合成的抑制作用比亲本卡那霉素差42 - 640倍，而它们对DNA促旋酶和拓扑异构酶IV的抑制活性与环丙沙星相似。与单独使用组分药物或其1:1混合物相比，这些杂合体在大肠杆菌和枯草芽孢杆菌中均显示出显著延缓耐药性产生的效果。更普遍地说，数据表明氨基糖苷类 - 氟喹诺酮杂合体的拮抗组合可产生能减缓/防止耐药性出现的新化合物。
