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.

Keywords: Antibiotics, antibacterial compounds, HTS, translation inhibition, furanocoumarins, ribosome.

Ventola, C.L. The antibiotic resistance crisis: part 1: Causes and threats. P&T, 2015, 40(4), 277-283.
[PMID: 25859123]
Fernandes, P.; Martens, E. Antibiotics in late clinical development. Biochem. Pharmacol., 2017, 133, 152-163.
[http://dx.doi.org/10.1016/j.bcp.2016.09.025] [PMID: 27687641]
DiMasi, J.A.; Grabowski, H.G.; Hansen, R.W. The cost of drug development. N. Engl. J. Med., 2015, 372(20), 1972.
[http://dx.doi.org/10.1056/NEJMc1504317] [PMID: 25970070]
Ling, L.L.; Schneider, T.; Peoples, A.J.; Spoering, A.L.; Engels, I.; Conlon, B.P.; Mueller, A.; Schäberle, T.F.; Hughes, D.E.; Epstein, S.; Jones, M.; Lazarides, L.; Steadman, V.A.; Cohen, D.R.; Felix, C.R.; Fetterman, K.A.; Millett, W.P.; Nitti, A.G.; Zullo, A.M.; Chen, C.; Lewis, K. A new antibiotic kills pathogens without detectable resistance. Nature, 2015, 517(7535), 455-459.
[http://dx.doi.org/10.1038/nature14098] [PMID: 25561178]
Charest, M.G.; Siegel, D.R.; Myers, A.G. Synthesis of (-)-tetracycline. J. Am. Chem. Soc., 2005, 127(23), 8292-8293.
[http://dx.doi.org/10.1021/ja052151d] [PMID: 15941256]
Seiple, I.B.; Zhang, Z.; Jakubec, P.; Langlois-Mercier, A.; Wright, P.M.; Hog, D.T.; Yabu, K.; Allu, S.R.; Fukuzaki, T.; Carlsen, P.N.; Kitamura, Y.; Zhou, X.; Condakes, M.L.; Szczypiński, F.T.; Green, W.D.; Myers, A.G. A platform for the discovery of new macrolide antibiotics. Nature, 2016, 533(7603), 338-345.
[http://dx.doi.org/10.1038/nature17967] [PMID: 27193679]
Andrei, S.; Valeanu, L.; Stefan, M-G. New FDA approved antibacterial drugs: 2015-2017. Discoveries (Craiova),, 2018, 6e81.
Greig, S.L. Obiltoxaximab: First global approval. Drugs, 2016, 76(7), 823-830.
[http://dx.doi.org/10.1007/s40265-016-0577-0] [PMID: 27085536]
Navalkele, B.D.; Chopra, T. Bezlotoxumab: an emerging monoclonal antibody therapy for prevention of recurrent Clostridium difficile infection. Biologics, 2018, 12, 11-21.
[http://dx.doi.org/10.2147/BTT.S127099] [PMID: 29403263]
Jorgensen, S.C.J.; Mercuro, N.J.; Davis, S.L.; Rybak, M.J. Delafloxacin: Place in therapy and review of microbiologic, clinical and pharmacologic properties. Infect. Dis. Ther., 2018, 7(2), 197-217.
[http://dx.doi.org/10.1007/s40121-018-0198-x] [PMID: 29605887]
Rosen, T.; Albareda, N.; Rosenberg, N.; Alonso, F.G.; Roth, S.; Zsolt, I.; Hebert, A.A. Efficacy and safety of ozenoxacin cream for treatment of adult and pediatric patients with impetigo: a randomized clinical trial. JAMA Dermatol., 2018, 154(7), 806-813.
[http://dx.doi.org/10.1001/jamadermatol.2018.1103] [PMID: 29898217]
Kaye, K.S.; Bhowmick, T.; Metallidis, S.; Bleasdale, S.C.; Sagan, O.S.; Stus, V.; Vazquez, J.; Zaitsev, V.; Bidair, M.; Chorvat, E.; Dragoescu, P.O.; Fedosiuk, E.; Horcajada, J.P.; Murta, C.; Sarychev, Y.; Stoev, V.; Morgan, E.; Fusaro, K.; Griffith, D.; Lomovskaya, O.; Alexander, E.L.; Loutit, J.; Dudley, M.N.; Giamarellos-Bourboulis, E.J. Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial. JAMA, 2018, 319(8), 788-799.
[http://dx.doi.org/10.1001/jama.2018.0438] [PMID: 29486041]
Zeitlinger, M.; Schwameis, R.; Burian, A.; Burian, B.; Matzneller, P.; Müller, M.; Wicha, W.W.; Strickmann, D.B.; Prince, W. Simultaneous assessment of the pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary epithelial lining fluid. J. Antimicrob. Chemother., 2016, 71(4), 1022-1026.
[http://dx.doi.org/10.1093/jac/dkv442] [PMID: 26747098]
Biedenbach, D.J.; Bouchillon, S.K.; Hackel, M.; Miller, L.A.; Scangarella-Oman, N.E.; Jakielaszek, C.; Sahm, D.F. In vitro activity of gepotidacin, a novel triazaacenaphthylene bacterial topoisomerase inhibitor, against a broad spectrum of bacterial pathogens. Antimicrob. Agents Chemother., 2016, 60(3), 1918-1923.
[http://dx.doi.org/10.1128/AAC.02820-15] [PMID: 26729499]
Alirol, E.; Wi, T.E.; Bala, M.; Bazzo, M.L.; Chen, X-S.; Deal, C.; Dillon, J.R.; Kularatne, R.; Heim, J.; Hooft van Huijsduijnen, R.; Hook, E.W.; Lahra, M.M.; Lewis, D.A.; Ndowa, F.; Shafer, W.M.; Tayler, L.; Workowski, K.; Unemo, M.; Balasegaram, M. Multidrug-resistant gonorrhea: A research and development roadmap to discover new medicines. PLoS Med., 2017, 14(7)e1002366
[http://dx.doi.org/10.1371/journal.pmed.1002366] [PMID: 28746372]
Srinivas, N.; Jetter, P.; Ueberbacher, B.J.; Werneburg, M.; Zerbe, K.; Steinmann, J.; Van der Meijden, B.; Bernardini, F.; Lederer, A.; Dias, R.L.A.; Misson, P.E.; Henze, H.; Zumbrunn, J.; Gombert, F.O.; Obrecht, D.; Hunziker, P.; Schauer, S.; Ziegler, U.; Käch, A.; Eberl, L.; Riedel, K.; DeMarco, S.J.; Robinson, J.A. Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science, 2010, 327(5968), 1010-1013.
[http://dx.doi.org/10.1126/science.1182749] [PMID: 20167788]
Novack, G.D. Eyes on new product development: Trabecular meshwork. J. Ocul. Pharmacol. Ther., 2014, 30(2-3), 83-84.
[http://dx.doi.org/10.1089/jop.2014.1505] [PMID: 24697264]
Hafkin, B.; Kaplan, N.; Murphy, B. Efficacy and Safety of AFN-1252, the first Staphylococcus-specific antibacterial agent, in the treatment of acute bacterial skin and skin structure infections, including those in patients with significant comorbidities. Antimicrob. Agents Chemother., 2015, 60(3), 1695-1701.
[http://dx.doi.org/10.1128/AAC.01741-15] [PMID: 26711777]
VNRX-5133 SAD/MAD Safety and PK in Healthy Adult Volunteers 2017.https://clinicaltrials.gov/ct2/show/NCT02955459
Woolhouse, M.; Waugh, C.; Perry, M.R.; Nair, H. Global disease burden due to antibiotic resistance - state of the evidence. J. Glob. Health, 2016, 6(1)010306
[http://dx.doi.org/10.7189/jogh.06.010306] [PMID: 27350872]
O’Neill, J. The review on antimicrobial resistance; AMR Review: UK, 2014.
Osterman, I.A.; Komarova, E.S.; Shiryaev, D.I.; Korniltsev, I.A.; Khven, I.M.; Lukyanov, D.A.; Tashlitsky, V.N.; Serebryakova, M.V.; Efremenkova, O.V.; Ivanenkov, Y.A.; Bogdanov, A.A.; Sergiev, P.V.; Dontsova, O.A. 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(12), 7481-7489.
[http://dx.doi.org/10.1128/AAC.02117-16] [PMID: 27736765]
Baba, T.; Mori, H. The construction of systematic in-frame, single-gene knockout mutant collection in Escherichia coli K-12. Methods Mol. Biol., 2008, 416, 171-181.
[http://dx.doi.org/10.1007/978-1-59745-321-9_11] [PMID: 18392967]
Komarova Andreyanova, E.S.; Osterman, I.A.; Pletnev, P.I.; Ivanenkov, Y.A.; Majouga, A.G.; Bogdanov, A.A.; Sergiev, P.V. 2-Guanidino-quinazolines as a novel class of translation inhibitors. Biochimie, 2017, 133, 45-55.
[http://dx.doi.org/10.1016/j.biochi.2016.11.008] [PMID: 28011211]
ChemoSoft. Chemical Diversity Labs, Inc, 2007.
Molecular Operating Environment (MOE), 2013.08 Chemical Computing Group ULC.,, 2018.
Osterman, I.A.; Khabibullina, N.F.; Komarova, E.S.; Kasatsky, P.; Kartsev, V.G.; Bogdanov, A.A.; Dontsova, O.A.; Konevega, A.L.; Sergiev, P.V.; Polikanov, Y.S. Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state. Nucleic Acids Res., 2017, 45(12), 7507-7514.
[http://dx.doi.org/10.1093/nar/gkx413] [PMID: 28505372]
Wiegand, I.; Hilpert, K.; Hancock, R.E.W. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat. Protoc., 2008, 3(2), 163-175.
[http://dx.doi.org/10.1038/nprot.2007.521] [PMID: 18274517]
Zgurskaya, H.I.; Löpez, C.A.; Gnanakaran, S. Permeability barrier of gram-negative cell envelopes and approaches to bypass it. ACS Infect. Dis., 2015, 1(11), 512-522.
[http://dx.doi.org/10.1021/acsinfecdis.5b00097] [PMID: 26925460]
Richter, M.F.; Drown, B.S.; Riley, A.P.; Garcia, A.; Shirai, T.; Svec, R.L.; Hergenrother, P.J. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature, 2017, 545(7654), 299-304.
[http://dx.doi.org/10.1038/nature22308] [PMID: 28489819]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy