Sulik Michał, Stępień Karolina, Stefańska Joanna, Huczyński Adam, Antoszczak Michał
Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.
Department of Pharmaceutical Microbiology, Centre for Preclinical Research and Technology (CePT), Faculty of Pharmacy, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
Bioorg Med Chem Lett. 2020 May 1;30(9):127062. doi: 10.1016/j.bmcl.2020.127062. Epub 2020 Feb 24.
The increasing challenge of antibiotic resistance stimulates the search for novel antibacterial agents, especially such that would be effective against multi-drug resistant bacterial strains. Fortunately, natural compounds are excellent sources of potentially new drug leads. Particularly interesting in this context are polyether antibiotic salinomycin (SAL) and its semi-synthetic derivatives, as they exhibit large spectrum of bioactivity. We synthesized and evaluated the antibacterial activity of a series of SAL analogs; four singly (2-3, 15, 17) and two doubly modified (16, 18) derivatives were found to show excellent inhibitory activity not only against planktonic Gram(+) bacterial cells, but also towards select strains of methicillin-resistant staphylococci with the MIC values of 1-4 µg mL. Of note, the most promising candidates were more effective in preventing bacterial biofilm formation than unmodified SAL and a commonly used antibiotic - ciprofloxacin. Furthermore, we proved that rational modification of C20 hydroxyl of SAL may reduce genotoxic properties of the obtained analogs. Mechanistically, the structure-activity relationship studies suggested that electroneutral transport mechanism could be beneficial in terms of ensuring high antibacterial activity of SAL derivatives.
抗生素耐药性带来的挑战日益增加，这促使人们寻找新型抗菌剂，尤其是对多重耐药菌株有效的抗菌剂。幸运的是，天然化合物是潜在新药先导物的极佳来源。在这种情况下，特别有趣的是聚醚抗生素沙利霉素（SAL）及其半合成衍生物，因为它们具有广泛的生物活性。我们合成并评估了一系列SAL类似物的抗菌活性；发现四种单修饰（2-3、15、17）和两种双修饰（16、18）衍生物不仅对浮游革兰氏阳性细菌细胞具有优异的抑制活性，而且对耐甲氧西林葡萄球菌的某些菌株也有抑制作用，其最低抑菌浓度（MIC）值为1-4μg/mL。值得注意的是，最有前景的候选物在预防细菌生物膜形成方面比未修饰的SAL和常用抗生素环丙沙星更有效。此外，我们证明对SAL的C20羟基进行合理修饰可降低所得类似物的遗传毒性。从机制上讲，构效关系研究表明，电中性转运机制可能有助于确保SAL衍生物具有高抗菌活性。
