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Identification of pyrrolo-pyridine derivatives as novel class of antibacterials

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Abstract

A series of 5-oxo-4H-pyrrolo[3,2-b]pyridine derivatives was identified as novel class of highly potent antibacterial agents during an extensive large-scale high-throughput screening (HTS) program utilizing a unique double-reporter system—pDualrep2. The construction of the reporter system allows us to perform visual inspection of the underlying mechanism of action due to two genes—Katushka2S and RFP—which encode the proteins with different imaging signatures. Antibacterial activity of the compounds was evaluated during the initial HTS round and subsequent rescreen procedure. The most active molecule demonstrated a MIC value of 3.35 µg/mL against E. coli with some signs of translation blockage (low Katushka2S signal) and no SOS response. The compound did not demonstrate cytotoxicity in standard cell viability assay. Subsequent structural morphing and follow-up synthesis may result in novel compounds with a meaningful antibacterial potency which can be reasonably regarded as an attractive starting point for further in vivo investigation and optimization.

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References

  1. Brown ED, Wright GD (2016) Antibacterial drug discovery in the resistance era. Nature 529:336–343. https://doi.org/10.1038/nature17042

    Article  CAS  PubMed  Google Scholar 

  2. Inglese J, Auld DS (2008) High throughput screening (HTS) techniques: applications in chemical biology. In: Wiley encyclopedia of chemical biology. https://doi.org/10.1002/9780470048672.wecb223

  3. Silver LL (2011) Challenges of antibacterial discovery. Clin Microbiol Rev 24:71. https://doi.org/10.1128/CMR.00030-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McGovern SL, Caselli E, Grigorieff N, Shoichet BK (2002) A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J Med Chem 45:1712–1722. https://doi.org/10.1021/jm010533y

    Article  CAS  PubMed  Google Scholar 

  5. Rishton GM (1997) Reactive compounds and in vitro false positives in HTS. Drug Discov Today 2:382–384. https://doi.org/10.1016/S1359-6446(97)01083-0

    Article  CAS  Google Scholar 

  6. Baell JB, Holloway GA (2010) New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 53:2719–2740. https://doi.org/10.1021/jm901137j

    Article  CAS  PubMed  Google Scholar 

  7. Brown DG, Lister T, May-Dracka TL (2014) New natural products as new leads for antibacterial drug discovery. Bioorg Med Chem Lett 24:413–418. https://doi.org/10.1016/j.bmcl.2013.12.059

    Article  CAS  PubMed  Google Scholar 

  8. Eisenstein BI, Oleson FB Jr, Baltz RH (2010) Daptomycin: from the mountain to the clinic, with essential help from Francis Tally, MD. Clin Infect Dis 50(Suppl 1):S10–S15. https://doi.org/10.1086/647938

    Article  CAS  PubMed  Google Scholar 

  9. Gerber M, Ackermann G (2008) OPT-80, a macrocyclic antimicrobial agent for the treatment of Clostridium difficile infections: a review. Expert Opin Investig Drugs 17:547–553. https://doi.org/10.1517/13543784.17.4.547

    Article  CAS  PubMed  Google Scholar 

  10. WHO publishes list of bacteria for which new antibiotics are urgently needed. In: World Health Organization. http://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed. Accessed 22 Nov 2018

  11. Singh P, Kumari R, Lal R (2017) Bedaquiline: fallible hope against drug resistant tuberculosis. Indian J Microbiol 57:371–377. https://doi.org/10.1007/s12088-017-0674-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu Y, Matsumoto M, Ishida H et al (2018) Delamanid: from discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB). Tuberculosis 111:20–30. https://doi.org/10.1016/j.tube.2018.04.008

    Article  CAS  PubMed  Google Scholar 

  13. Osterman IA, Komarova ES, Shiryaev DI et al (2016) Sorting out antibiotics’ mechanisms of action: a double fluorescent protein reporter for high-throughput screening of ribosome and DNA biosynthesis inhibitors. Antimicrob Agents Chemother 60:7481–7489. https://doi.org/10.1128/AAC.02117-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chemical Supplier—Enamine. https://enamine.net/. Accessed 3 Dec 2018

  15. ChemDiv—Contract Research Organization. In: Chemdiv. http://chemdiv.com/. Accessed 3 Dec 2018

  16. InterBioScreen ltd. | Compound Libraries. In: InterBioScreen ltd. | Compound Libraries. https://www.ibscreen.com. Accessed 3 Dec 2018

  17. Trepalin SV, Yarkov AV (2001) CheD: chemical database compilation tool, Internet server, and client for SQL servers. J Chem Inf Comput Sci 41:100–107. https://doi.org/10.1021/ci000039n

    Article  CAS  PubMed  Google Scholar 

  18. Wiegand I, Hilpert K, Hancock REW (2008) Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc 3:163–175. https://doi.org/10.1021/ci000039n

    Article  CAS  Google Scholar 

  19. SwissADME. http://www.swissadme.ch/. Accessed 20 Jan 2019

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Acknowledgements

The authors would like to kindly acknowledge the Ministry of Education and Science of the Russian Federation, government Grant 20.9907.2017/VU (expert opinion, discussion and manuscript preparation) and Russian Science Foundation №17-74-30012, IBG RAS Ufa (biological evaluation and compound selection). Authors thank Maria M. Puchinina for help during the preparation of the manuscript.

Author contributions

MSV, YAI and RSY have performed in silico screening procedures. MSV, YAI and AAA wrote the manuscript. DSB and GIF have collected and prepared the databases. IAO, PVS, VAA, AVA, VAT and OAD sorted out the antibiotics’ mechanisms of action by means of a double fluorescent protein reporter for high-throughput screening of ribosome and DNA biosynthesis inhibitors and edited the manuscript. AEM, RAP, SYM collected, pre-processed and analyzed the data. DAS, KSK, AVC, AKB and AAS designed and performed experiments on measuring MIC. LFZ, MAM, ZRZ, VGK and YVV performed experiments on cell viability.

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Correspondence to Mark S. Veselov.

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Veselov, M.S., Ivanenkov, Y.A., Yamidanov, R.S. et al. Identification of pyrrolo-pyridine derivatives as novel class of antibacterials. Mol Divers 24, 233–239 (2020). https://doi.org/10.1007/s11030-019-09946-3

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