Shapovalova Kseniya S, Zatonsky Georgy V, Razumova Elizaveta A, Ipatova Daria A, Lukianov Dmitrii A, Sergiev Petr V, Grammatikova Natalia E, Tikhomirov Alexander S, Shchekotikhin Andrey E
Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, Moscow 119991, Russia.
Antibiotics (Basel). 2024 Dec 6;13(12):1191. doi: 10.3390/antibiotics13121191.
Aminoglycosides are one of the first classes of natural antibiotics which have not lost relevance due to their broad spectrum of action against Gram-positive, Gram-negative bacteria and mycobacteria. The high growth rate of antimicrobial resistance (AMR) together with the severe side effects of aminoglycosides increase the importance of developing improved semisynthetic derivatives. In this work, we proposed a synthetic route to new tobramycin derivatives modified at the 6″-position with aminoalkylamine or guanidinoalkylamine residues. The antibacterial activity of the new compounds against reference strains of microorganisms was comparable to the parental tobramycin. In striking contrast to tobramycin (resistance index, >256), its 6″-modified derivatives were significantly more potent against resistant clinical isolates of strains (resistance index = 4-16) and they demonstrated a promising AMR circumvention in strains associated with mutations in the fusA gene encoding elongation factor G. All the obtained tobramycin derivatives exhibited reduced cytotoxicity for the eukaryotic HEK293T cells compared to the tobramycin and thereby they potentially may have improved therapeutic index. The proposed modification of the 6″-position of tobramycin does not change the mechanism of aminoglycoside's antibacterial activity: new compounds induced translation errors which resulted in the inhibition of protein synthesis in bacterial cells. Taken together, we can suggest that further modifications of the 6″-position of tobramycin may be beneficial for circumvention of AMR to aminoglycosides or used for conjugation with other molecules of interest.
氨基糖苷类是最早的一类天然抗生素，由于其对革兰氏阳性菌、革兰氏阴性菌和分枝杆菌具有广泛的抗菌作用，至今仍具有重要意义。抗菌耐药性（AMR）的高增长率以及氨基糖苷类药物的严重副作用，增加了开发改良半合成衍生物的重要性。在这项工作中，我们提出了一条合成路线，用于制备在6″位修饰有氨基烷基胺或胍基烷基胺残基的新妥布霉素衍生物。新化合物对微生物参考菌株的抗菌活性与母体妥布霉素相当。与妥布霉素形成鲜明对比的是（耐药指数>256），其6″位修饰的衍生物对耐药临床分离菌株（耐药指数=4-16）的活性明显更强，并且在与编码延伸因子G的fusA基因突变相关的菌株中显示出有前景的AMR规避能力。与妥布霉素相比，所有获得的妥布霉素衍生物对真核HEK293T细胞的细胞毒性均有所降低，因此它们可能具有更高治疗指数。所提出的对妥布霉素6″位的修饰并未改变氨基糖苷类抗菌活性的机制：新化合物诱导翻译错误，从而抑制细菌细胞中的蛋白质合成。综上所述，我们可以认为对妥布霉素6″位的进一步修饰可能有利于规避对氨基糖苷类的AMR，或用于与其他感兴趣的分子进行偶联。
