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 reveal
compounds having antibacterial activity. This construction is based on two genes of Katushka2S
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 smallmolecule
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 structure.
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.