Tetrahydrocarbazoles as novel class of DNA biosynthesis inhibitors in bacteria

Yan A. Ivanenkov, Ilya A. Osterman, Ekaterina S. Komarova, Alexey A. Bogdanov, Petr V. Sergiev, Olga A. Dontsova, Alina A. Sofronova, Victor A. Terentiev, Gleb I. Filkov, Renat S. Yamidanov, Alexander G. Majouga, Dmitry S. Bezrukov, Ekaterina V. Deyneka, Dmitry A. Skvortsov

Результат исследований: Вклад в журналСтатьярецензирование

3 Цитирования (Scopus)


Background: High-throughput screening (HTS) of large-compound libraries is a convenient and cost-effective tool for novel drug discovery. However, in many cases, HTS platforms are not well adapted to perform cell-based screening assay with simultaneous identification of the mechanism of action for active compounds. Methods: Previously, we have described a unique double-reporter system that can be used to re-veal compounds having antibacterial activity. This construction is based on two genes of Katu-shka2S and RFP that encode proteins with different imaging signature. The upregulated expression of the first gene attributes directly to translation inhibition in prokaryotes while the high expression of the second one is unambiguously associated with DNA biosynthesis restriction (SOS-response). Results: In the current work, we have applied this system for the identification of novel small-molecule compounds with antibacterial activity in HTS scale. Compounds were selected from the ChemDiv in-house collection (of total 47K molecules) following the maximum diversity in struc-ture. Based on the obtained results, we have revealed a small series of tetrahydrocarbazole derivatives with antibacterial activity. The hit compound inhibited bacterial growth with a MIC value of 21 µg/ml and blocked DNA biosynthesis. No activity towards translation has been observed. In spite of a relatively moderate potency, as compared to the control sample (erythromycin, MIC=3 µg/ml), this molecule provides good selectivity index (SI>333, HEK239). Conclusion: Tetrahydrocarbazole derivatives can be properly regarded as an attractive starting point for further development and optimization.

Язык оригиналаАнглийский
Страницы (с-по)121-127
Число страниц7
ЖурналAnti-Infective Agents
Номер выпуска2
СостояниеОпубликовано - 2020


Подробные сведения о темах исследования «Tetrahydrocarbazoles as novel class of DNA biosynthesis inhibitors in bacteria». Вместе они формируют уникальный семантический отпечаток (fingerprint).