Bescós-Ramo Sara, Gámez Enrique, Encabo-Berzosa María Del Mar, Piñol Milagros, Oriol Luis, Arruebo Manuel
Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza, 50009, Spain.
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, C/ Pedro Cerbuna 12, Zaragoza, 50009, Spain.
BMC Chem. 2025 Jun 9;19(1):162. doi: 10.1186/s13065-025-01538-7.
Catechol moieties have been covalently coupled to the last-resort polypeptide antibiotic colistin via esterification and amidation reactions, inspired by the superior antimicrobial action of cefiderocol, i.e., a catechol-substituted siderophore cephalosporin. Among the tested strategies, the incorporation of the catechol motif by amidation reduces by 50% the minimum concentration to inhibit the growth of a clinical strain of uropathogenic Escherichia coli (E. coli) in its planktonic form. Its minimum bactericidal concentration is reduced by 25% after chemical modification. The tested modified antibiotic did not show cytotoxicity against human fibroblasts and keratinocytes at bactericidal doses. Additionally, due to the potential nephrotoxicity of colistin, the cytotoxicity of this catechol-substituted siderophore colistin was evaluated in a 3D model of human renal organoids showing no cytotoxicity at the doses tested. The chemical incorporation of catechol groups to existing antibiotics can reduce the doses to exert a fast antimicrobial action reducing the chances to develop antibiotic resistance.
受头孢地尔（一种儿茶酚取代的铁载体头孢菌素）卓越抗菌作用的启发，儿茶酚部分已通过酯化和酰胺化反应与最后手段的多肽抗生素黏菌素共价偶联。在测试的策略中，通过酰胺化引入儿茶酚基序可将抑制临床尿路致病性大肠杆菌（大肠杆菌）浮游形式生长的最低浓度降低50%。化学修饰后其最低杀菌浓度降低了25%。测试的修饰抗生素在杀菌剂量下对人成纤维细胞和角质形成细胞未显示出细胞毒性。此外，由于黏菌素具有潜在的肾毒性，在人肾类器官的3D模型中评估了这种儿茶酚取代的铁载体黏菌素的细胞毒性，在所测试的剂量下未显示出细胞毒性。将儿茶酚基团化学引入现有抗生素可降低发挥快速抗菌作用所需的剂量，减少产生抗生素耐药性的机会。
