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Mononuclear copper(II) complexes of the macrolide antibiotics tylosin and tilmicosin

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Abstract

The 16-membered macrolide antibiotics tylosin (HTyl) and tilmicosin (HTilm) react with Cu(II) to form isostructural mononuclear complexes of composition [CuL2] (L = Tyl− (1), Tilm− (2)). Reactions take place in aqueous alkaline solutions, at molar metal-to-ligand ratio ranging from 1:10 to 1:2. The coordination species obtained were characterized by physico-chemical and spectroscopic methods. Experimental data and quantum chemical calculations revealed that the copper atom is placed in a square-planar environment and the main chromophore unit is of composition [CuN2O2]. The complexes consist of two ligand monoanions acting in a bidentate coordination mode via the tertiary nitrogen atom and the deprotonated hydroxyl group of the mycaminosyl substituent. The antibacterial assay of the macrolides and their mononuclear copper(II) complexes 1–2 against Gram-positive microorganisms demonstrated that the new coordination compound of tilmicosin exhibits enhanced activity compared to that of the parent ligand.

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References

  1. Dinos GP (2017) The macrolide antibiotic renaissance. Br J Pharmacol 174:2967–2983. https://doi.org/10.1111/bph.13936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Khaliq S, Ghauri MA, Akhtar K (2014) Characterization of mutations in regulatory genes of Tyl cluster leading to overexpression of tylosin in mutant γ-1 of Streptomyces fradiae NRRL-2702. Appl Microbiol Biotechnol 98:785–793. https://doi.org/10.1007/s00253-013-5317-8

    Article  CAS  PubMed  Google Scholar 

  3. Arsic B, Barber J, Čikoš A, Mladenovic M, Stankovic N, Novak P (2018) 16-membered macrolide antibiotics: a review. Int J Antimicrob Agents 51:283–298. https://doi.org/10.1016/j.ijantimicag.2017.05.020

    Article  CAS  PubMed  Google Scholar 

  4. Kirst HA (2002) Introduction to the macrolide antibiotics. In: Schllnfeld W, Kirst HA (eds) Macrolide antibiotics. Birkhäuser Verlag, Basel. https://doi.org/10.1007/978-3-0348-8105-0_1

    Chapter  Google Scholar 

  5. Cui W, Ma S (2011) Recent advances in the field of 16-membered macrolide antibiotics. Mini Rev Med Chem 11:1009–1018

    Article  CAS  Google Scholar 

  6. Champney WS, Tober CL (2000) Specific inhibition of 50S ribosomal subunit formation in Staphylococcus aureus cells by 16-membered macrolide, lincosamide, and streptogramin B Antibiotics. Curr Microbiol 41:126–135. https://doi.org/10.1007/s002840010106

    Article  CAS  PubMed  Google Scholar 

  7. Thompson TS, Pernal SF, Noot DK, Melathopoulos AP, van den Heevera JP (2007) Degradation of incurred tylosin to desmycosin—implications for residue analysis of honey. Anal Chim Acta 586:304–311. https://doi.org/10.1016/j.aca.2006.09.043

    Article  CAS  PubMed  Google Scholar 

  8. Jordan FT, Knight D (1984) The minimum inhibitory concentration of kitasamycin, tylosin and tiamulin for Mycoplasma gallisepticum and their protective effect on infected chicks. Avian Pathol 13:151–162. https://doi.org/10.1080/03079458408418520

    Article  CAS  PubMed  Google Scholar 

  9. Jordan FT, Horrocks BK (1996) The minimum inhibitory concentration of tilmicosin and tylosin for Mycoplasma gallisepticum and Mycoplasma synoviae and a comparison of their efficacy in the control of Mycoplasma gallisepticum infection in broiler chicks. Avian Dis 40:326-334

    Article  CAS  Google Scholar 

  10. Stakenborg T, Vicca J, Butaye P, Maes D, Minion FC, Peeters J, De Kruif A, Haesebrouck F (2005) Characterization of in vivo acquired resistance of Mycoplasma hyopneumoniae to macrolides and lincosamides. Microb Drug Resist 11:290–294. https://doi.org/10.1089/mdr.2005.11.290

    Article  CAS  PubMed  Google Scholar 

  11. Wang S, Yang Y, Zhao Y, Zhao H, Bai J, Chen J, Zhou Y, Wang C, Li Y (2016) Sub-MIC tylosin inhibits Streptococcus suis biofilm formation and results in differential protein expression. Front Microbiol 7:384. https://doi.org/10.3389/fmicb.2016.00384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Committee for veterinary medicinal products (1997) Tilmicosin (extension to chicken). EMEA/MRL/318/97. https://www.ema.europa.eu/en/documents/mrl-report/tilmicosin-extension-chicken-summary-report-1-committee-veterinary-medicinal-products_en.pdf

  13. Ose EE (1987) In vitro antibacterial properties of EL-870, a new semi-synthetic macrolide antibiotic. J Antibiot (Tokyo) 40:190–194. https://doi.org/10.7164/antibiotics.40.190

    Article  CAS  Google Scholar 

  14. Kirst HA (1997) Macrolide antibiotics in food-animal health. Expert Opin Investig Drugs 6:103–118. https://doi.org/10.1517/13543784.6.2.103

    Article  CAS  PubMed  Google Scholar 

  15. Iakovidis I, Delimaris I, Piperakis SM (2011) Copper and its complexes in medicine: a biochemical approach, Mol Biol Int 2011: Article ID 594529. https://doi.org/10.4061/2011/594529

  16. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz AF, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini, F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JAJr, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2016) Gaussian 16, Revision C.01, Gaussian, Inc., Wallingford CT

  17. Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3093. https://doi.org/10.1021/cr9904009

    Article  CAS  PubMed  Google Scholar 

  18. Reed AE, Curtiss LA, Weinhold F (1988) Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem Rev 88:899–926. https://doi.org/10.1021/cr00088a005

    Article  CAS  Google Scholar 

  19. Wiitala KW, Hoye TR, Cramer C (2006) Hybrid density functional methods empirically optimized for the computation of 13C and 1H chemical shifts in acetone solution. J Chem Theory Comput 2:1085–1092. https://doi.org/10.1021/ct6001016

    Article  CAS  PubMed  Google Scholar 

  20. Neese F (2017) Software update: the ORCA program system, version 4.0. Wiley Interdiscip Rev Comput Mol Sci 8:e1327. https://doi.org/10.1002/wcms.1327

    Article  Google Scholar 

  21. Wachters AJH (1970) Gaussian basis set for molecular wavefunctions containing third row atoms. J Chem Phys 52:1033–1036. https://doi.org/10.1063/1.1673095

    Article  CAS  Google Scholar 

  22. Andrews JM (2001) Determination of minimum inhibitory concentrations. J Antimicrob Chemother 48(Suppl 1):5–16. https://doi.org/10.1093/jac/48.suppl_1.5

    Article  CAS  PubMed  Google Scholar 

  23. Bontchev PR, Pantcheva IN (2002) Copper(II) complexes of blood pressure active drugs. Trans Metal Chem 27:1–21. https://doi.org/10.1023/A:1013466529495

    Article  CAS  Google Scholar 

  24. Seppälä P, Sillanpää R, Lehtonen A (2017) Structural diversity of copper(II) amino alcoholate complexes. Coord Chem Rev 347:98–114. https://doi.org/10.1016/j.ccr.2017.06.022

    Article  CAS  Google Scholar 

  25. Hathaway BJ, Billing DE (1970) The electronic properties and stereochemistry of mononuclear complexes of the copper(II) ion. Coord Chem Rev 5:143–207. https://doi.org/10.1016/S0010-8545(00)80135-6

    Article  CAS  Google Scholar 

  26. Kirst HA, Donoho AL, Creemer LC, Wind JA, Berry DM, Occolowitz JL, Paschal JW (1994) Identification and synthesis of products isolated during metabolism studies of tilmicosin. J Agric Food Chem 42:1219–1222. https://doi.org/10.1021/jf00041a032

    Article  CAS  Google Scholar 

  27. Debono M, Willard KE, Kirst HA, Wind JA, Crouse GD, Tao EV, Vicenzi JT, Counter FT, Ot JL, Ose EE, Omura S (1989) Synthesis and antimicrobial evaluation of 20-deoxo-20-(3,5-dimethylpiperidin-l-yl)desmycosin (tilmicosin, EL-870) and related cyclic amino derivatives. J Antibiot (Tokyo) 4:1253–1267. https://doi.org/10.7164/antibiotics.42.1253

    Article  Google Scholar 

  28. Dokič S, Vajtner Z, Lopotar N, Mruoš-Sermec D, Kamenar D, Nagl A (1995) Complexes of azithromycin with some divalent metal ions. Croat Chim Acta 68:375–381

    Google Scholar 

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Acknowledgements

This work was financially supported by Sofia University “St. Kliment Ohridski” (Grant No. 80-10-143/2021). Research equipment of Distributed Research Infrastructure INFRAMAT, part of the Bulgarian National Roadmap for Research Infrastructures, supported by the Bulgarian Ministry of Education and Science, was used in this investigation.

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Authors and Affiliations

  1. Faculty of Chemistry and Pharmacy, Sofia University “St. Kliment Ohridski”, 1, J. Bourchier Blvd., 1164, Sofia, Bulgaria

    Ivayla N. Pantcheva, Radoslava D. Stambolyiska, Nikolay N. Petkov & Alia V. Tadjer

  2. Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bontchev Str., build. 9, 1113, Sofia, Bulgaria

    Svetlana D. Simova

  3. Institute of General and Inorganic Chemistry, Bulgarian Academy of Sciences, , Acad. G. Bontchev Str., build. 11, 1113, Sofia, Bulgaria

    Radostina K. Stoyanova & Rositza R. Kukeva

  4. Research and Development Department, Biovet Ltd., 4550, Peshtera, Bulgaria

    Petar D. Dorkov

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  1. Ivayla N. Pantcheva
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  2. Radoslava D. Stambolyiska
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Correspondence to Ivayla N. Pantcheva.

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Pantcheva, I.N., Stambolyiska, R.D., Petkov, N.N. et al. Mononuclear copper(II) complexes of the macrolide antibiotics tylosin and tilmicosin. Transit Met Chem 47, 67–76 (2022). https://doi.org/10.1007/s11243-022-00491-x

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