Introduction: A variety of organic compounds has been reported to have antibacterial activity.
However, antimicrobial resistance is one of the main problems of current anti-infective therapy, and the
development of novel antibacterials is one of the main challenges of current drug discovery.
Methods: Using our previously developed dual-reporter High-Throughput Screening (HTS) platform, we
identified a series of furanocoumarins as having high antibacterial activity. The construction of the reporter
system allows us to differentiate three mechanisms of action for the active compounds: inhibition of
protein synthesis (induction of Katushka2S), DNA damaging (induction of RFP) or other (inhibition of
bacterial growth without reporter induction).
Results: Two primary hit-molecules of furanocoumarin series demonstrated relatively low MIC values
comparable to that observed for Erythromycin (Ery) against E. coli and weakly induced both reporters.
Dose-dependent translation inhibition was shown using in vitro luciferase assay, however it was not
confirmed using C14-test. A series of close structure analogs of the identified hits was obtained and
investigated using the same screening platform. Compound 19 was found to have slightly lower MIC value
(15.18 µM) and higher induction of Katushka2S reporter in contrast to the parent structures. Moreover,
translation blockage was clearly identified using both in vitro luciferase assay and C14 test. The standard
cytotoxicity test revealed a relatively low cytotoxicity of the most active molecules.
Conclusion: High antibacterial activity in combination with low cytotoxicity was demonstrated for a series
of furanocoumarins. Further optimization of the described structures may result in novel and attractive lead
compounds with promising antibacterial efficiency.