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Shalygina V. V., Vlasova E. N., Anan'eva E. P., Gurina S. V. Complexation of Polymyxin B1 Derivatives with Heparin. Izvestiya of Saratov University. New series. Series: Chemistry. Biology. Ecology, 2020, vol. 20, iss. 2, pp. 157-162. DOI: https://doi.org/10.18500/1816-9775-2020-20-2-157-162


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Russian

Complexation of Polymyxin B1 Derivatives with Heparin

Abstract

The method of coprecipitation from aqueous solutions at a neutral pH value was used to study the interaction of polymyxin B1 derivatives with sodium heparinate. They were compared with the initial unmodified antibiotic and with the initial antibiotic in a solution of the corresponding polymer, covalently unbound with it. It was observed that intense precipitation for an unmodified antibiotic took place at a 10-fold molar excess of the peptide by the base (the expected mole of heparin is 12000–16000, polymyxin B1 base – 1150), the temperature of 37° С and the low ionic strength of the solution. It was found that for the examined derivatives obtained by modifying polymyxin B1 at amino groups with synthetic water-soluble polymers, the amount of precipitate at the same pH level and ionic strength at any peptidesodium heparinate ratios was significantly less and did not depend on the temperature during the experiment. Using IR spectroscopy it was confirmed that both carboxyl and sulfamide groups of heparin were involved in complexation. Differences in the nature of the interaction of sodium heparinate with the initial peptide and its derivatives were revealed. The observed lower affinity of heparin binding to polymyxin B1 derivatives compared to the initial antibiotic was apparent due to decrease in the density of positive charge localization in their molecule as a result of modification of -NH2 groups.

References

1. N. S. Egorova, ed. Antibiotiki-polipeptidy: Struktura, funkciya i biosintez. [Antibiotics-Polypeptides: Structure, function, and biosynthesis]. Moscow, Izd-vo Mosk. un-ta, 1987. 264 p. (in Russian).
2. Shchetinin E. V. Polymyxins – New Approaches to the old Antimicrobial. Clinical Microbiology and Antimicrobial Chemoterapy, 2000, vol. 2, no. 3, pp. 68–73 (in Russian).
3. Nation R. L., Li J., Cars O., Couet W., Dudley M. N., Kaye K. S., Mouton J. W., Paterson D. L., Tam V. N., Theuretzbacher U., Tsuji B. T., Turnidge J. D. Framework for optimization of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus // Lancet Infect. Dis. 2015. Vol. 15, № 2. P. 225–234. DOI: https://doi.org/10.1016/S1473-30991470850-3
4. Zakuan Z. D., Suresh K. Rational use of intravenous polymyxin B and colistin: A review // Med. J. Malaysia. 2018. Vol. 73, № 5. P. 351–359.
5. Tsuji B. T., Poque J. M., Zavascki A. P., Paul M., Daikos G. L., Forrest A., Giacobbe D. R., Viscoli C., Giamarellou H., Karaiskos I., Kaye D., Mouton J. W., Tam V. H., Thamlikitkul V., Wunderink R. G., Li J., Nation R. L., Kaye K. S. International Consensus Guidelines for the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti – infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP) // Pharmacotherapy. 2019. Vol. 39, № 1. P. 10–39. DOI: https://doi.org/10.1002/phar.2209
6. Birkenmeier G., Nicklisch S., Pockelt C., Mossie A., Steger V., Glaser C., Hauschildt S., Usbeck E., Huse K., Sack U., Bauer M., Schafer A. Polymyxin B – Conjugated α2-Macroglobulin as an Adjunctive Therapy to Sepsis: Modes of Action and Impact on Lethality // J. Pharmacology and Experimental Therapeutics. 2006. Vol. 318, № 2. P. 762–771. DOI: https://doi.org/10/1124/jpet.106.104265
7. Zhao J., Cheah S-E., Roberts K. D., Nation R. L., Thompson P. E., Velkov T., Du Z., Johnson M. D., Li J. Transcriptomic analysis of the activity of a novel polymyxin against Staphylococcus aureus // mSphere. 2016. Vol. 1, № 4. P. e00119-16. DOI: https://doi.org/10.1128/mSphere.00119-16
8. Anan, eva E. P., Gajdukova V. A., Karavaeva A. V., Shalygina V. V. Comparative evaluation of antimicrobial activity of polymyxin B1 polymeric conjugates. J. Problems in Medical Mycology, 2018, vol. 20, no. 2, pp. 47–48 (in Russian).
9. Mulloy B., Hogwood J., Gray E., Lever R., Page C.P. Pharmacology of Heparin and Related Drugs // Pharmacol. Rev. 2016. Vol. 68, № 1. P. 76–141. DOI: https://doi.org/10.1124/pr.115.011247
10. Shalygina V. V., Vlasova E. N., Gaydukova V. A., Anan'eva E. P., Panarin E. F. Modifi cation of Polymyxin B1 by Water – Soluble Functional Copolymers of Vinyl Alcoho. Russian J. of General Chemistry, 2018, vol. 88, no. 6, pp. 1194–1198. DOI: https://doi.org/10.1134/S1070363218060233
11. Shalygina V. V., Vlasova E. N., Anan, eva E. P., Gaydukova V. A. Synthesis, physicochemical properties, and antimicrobial activity of polymyxin B1 conjugates with polyglutaraldehyde. Pharmaceutical Chemistry Journal, 2019, vol. 53, no. 2, pp. 134–138. DOI: https://doi.org/10.30906/0023-1134-2019-53-2-42-46
12. Stathakis N. E., Mosesson M. W. Interactions among Heparin, Cold – Insoluble Globulin, and Fibrinogen in Formation of the Heparin – Precipitable Fraction of Plasma // J. Clin. Invest. 1977. Vol. 60, № 4. P. 855–865. DOI: https://doi.org/10.1172/JCI108840
13. Conrad H. E. Heparin – Binding Proteins. San-Diego : Academic Press, 1998. 553 p.

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