The present report describes our efforts to identify new structural classes of compounds having promising antibacterial activity using previously published double-reporter system pDualrep2. This semi-automated high-throughput screening (HTS) platform has been applied to perform a large-scale screen of a diverse small-molecule compound library. We have selected a set of more than 125,000 molecules and evaluated them for their antibacterial activity. On the basis of HTS results, eight compounds containing 2-pyrazol-1-yl-thiazole scaffold exhibited moderate-to-high activity against ΔTolC Escherichia coli. Minimum inhibitory concentration (MIC) values for these molecules were in the range of 0.037–8 μg ml−1. The most active compound 8 demonstrated high antibacterial potency (MIC = 0.037 μg ml−1), that significantly exceed that measured for erythromycin (MIC = 2.5 μg ml−1) and was comparable with the activity of levofloxacin (MIC = 0.016 μg ml−1). Unfortunately, this compound showed only moderate selectivity toward HEK293 eukaryotic cell line. On the contrary, compound 7 was less potent (MIC = 0.8 μg ml−1) but displayed only slight cytotoxicity. Thus, 2-pyrazol-1-yl-thiazoles can be considered as a valuable starting point for subsequent optimization and morphing.
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DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ 2016;47:20–33.
Website. Available at: www.idsociety.org/Content.aspx?id=17577. Accessed 7 December 2018.
Singh N, et al. QSAR classification model for antibacterial compounds and its use in virtual screening. J Chem Inf Model. 2012;52:2559–69.
Gulland A. Antimicrobial resistance is now widespread, warns WHO. Br Med J. 2014;348:g3062–g3062.
Website. Available at: https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed 7 December 2018.
Kim CT, et al. Bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis: a multicentre cohort study in Korea. Eur Respir J. 2018;51:1702467.
Pontali E, et al. Combined treatment of drug-resistant tuberculosis with bedaquiline and delamanid: a systematic review. Eur Respir J. 2018;52:1800934.
Gerasyuto AI, et al. Discovery and optimization of indolyl-containing 4-hydroxy-2-pyridone type II DNA topoisomerase inhibitors active against multidrug resistant gram-negative bacteria. J Med Chem. 2018;61:4456–75.
Skepper CK, et al. Discovery and optimization of phosphopantetheine adenylyltransferase inhibitors with gram-negative antibacterial activity. J Med Chem. 2018;61:3325–49.
Chacko S, et al. Expanding benzoxazole-based inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitor structure–activity as potential antituberculosis agents. J Med Chem. 2018;61:4739–56.
De Schutter JW, Morrison JP, Morrison MJ, Ciulli A, Imperiali B. Targeting bacillosamine biosynthesis in bacterial pathogens: development of inhibitors to a bacterial amino-sugar acetyltransferase from Campylobacter jejuni. J Med Chem. 2017;60:2099–118.
Azzali E, et al. Substituted N-Phenyl-5-(2-(phenylamino)thiazol-4-yl)isoxazole-3-carboxamides are valuable antitubercular candidates that evade innate efflux machinery. J Med Chem. 2017;60:7108–22.
Panchaud P, et al. Discovery and optimization of isoquinoline ethyl ureas as antibacterial agents. J Med Chem. 2017;60:3755–75.
Osterman IA, et al. Sorting out antibiotics’ mechanisms of action: a double fluorescent protein reporter for high throughput screening of ribosome and DNA biosynthesis inhibitors. Antimicrob Agents Chemother. 2016;60:7481–9.
Komarova Andreyanova ES, et al. 2-Guanidino-quinazolines as a novel class of translation inhibitors. Biochimie. 2017;133:45–55.
ChemDiv - Contract Research Organization. Chemdiv. Available at: http://www.chemdiv.com/. Accessed 7 December 2018.
InterBioScreen ltd. Compound Libraries. InterBioScreen ltd. Compound Libraries. Available at: https://www.ibscreen.com. Accessed 7 December 2018.
EnamineStore. Available at: www.enaminestore.com/. Accessed 7 December 2018.
Osterman IA, et al. Attenuation-based dual-fluorescent-protein reporter for screening translation inhibitors. Antimicrob Agents Chemother. 2012;56:1774–83.
Schumacher SD, Hannemann F, Teese MG, Bernhardt R, Jose J. Autodisplay of functional CYP106A2 in Escherichia coli. J Biotechnol. 2012;161:104–12.
Wiegand I, Hilpert K, Hancock REW. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc. 2008;3:163–75.
SciFinder - Sign In. Available at: https://scifinder.cas.org/. Accessed 7 December 2018.
Website. Available at: https://integrity.thomson-pharma.com/. Accessed 7 December 2018.
EMBL-EBI. The European Bioinformatics Institute <EMBL-EBI. Available at https://www.ebi.ac.uk/. Accessed 4 December 2018.
Sammon JW. A nonlinear mapping for data structure. Anal IEEE Trans Comput C. 1969;18:401–9.
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 paper preparation) and Russian Science Foundation No. 17-74-30012, IBG RAS Ufa (biological evaluation and compound selection).
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Ivanenkov, Y.A., Yamidanov, R.S., Osterman, I.A. et al. 2-Pyrazol-1-yl-thiazole derivatives as novel highly potent antibacterials. J Antibiot 72, 827–833 (2019). https://doi.org/10.1038/s41429-019-0211-y