Prospects and Features of the Turbidimetric Analysis Method for Determining the Antimicrobial Activity of Peptides and Antibiotics of the Glycopeptide Series (Systematic Scoping Review)

Introduction. Antimicrobial peptides and antibiotics produced by microorganisms are the leading group in pharmaceuticalл78 production in most economically developed countries. These drugs used in the treatment of various infectious diseases are one of the broadest categories. In Russia, antimicrobial agents are included in the list of vital and essential drugs. Currently, the problem of import substitution is acute due to the current political situation, so strategies for replacing imported pharmaceutical substances with domestic ones are currently being actively developed. Quantitative determination of the quality of antibiotic drugs is the main task for enterprises producing these drugs. The methods used for these tasks, such as biological, diffusion, turbidimetric, spectroscopic and chromatographic analyzes, require timely improvement and modifications to increase their specificity, sensitivity and reproducibility, which ultimately determines the quality of the drug. 

Purpose. The aim of this scientific study is to collect theoretical data and analyze the scientific literature to review the sector of antimicrobial peptides and antibiotics produced by microorganisms, especially glycopeptide antibiotics. 

Materials and Methods. Theoretical analysis, comparative analysis of the collected information, SWOT analysis; criterial method for analyzing information sources. Results and discussion. This study examined biological methods, their relevance for some antibiotics, such as glycopeptides, due to their complex chemical structure, which complicates the use of physicochemical analysis methods. Analysis of scientific publications in Russian and foreign (English) languages, reflecting the features of the characteristics of the glycopeptide antibiotic - vancomycin, its antimicrobial action, a block diagram of its production and microbial synthesis. When writing this review, peer-reviewed articles, patents and other sources published between 2019 and 2024, in Russian and English, were used. The search was conducted based on the following keywords: «pharmaceutical market», «antimicrobial peptides», «glycopeptide antibiotics», «vancomycin», «agar diffusion method», «turbidimetry method». As a result of the search for information sources, 50 publications posted in foreign and Russian-language databases (PubMed, Google scholar, E-library, Cyberleninka, State Pharmacopoeia of the Russian Federation) were selected. 

Results. The dynamics of the modern pharmaceutical market of the antibiotic sector was analyzed, problem areas were identified, antibiotics produced by microorganisms were considered and a comparative analysis with antimicrobial peptides was carried out. The characteristics of the main group of glycopeptide antibiotics studied in this review, in particular vancomycin, are given. Its mechanism of antimicrobial action, technological block diagram of production and microbial synthesis at the molecular level are described. Pharmacopoeial methods for determining antimicrobial activity, namely the agar diffusion method and the turbidimetric method, are considered, a comparative analysis of these methods is carried out, and positive and negative aspects of standardization and control of antibiotic activity are identified.

1. Andriukov, B. G., Besednova, N. N., & Zaporozhets, T. S. (2022). On the 80th anniversary of the creation of gramicidin C: from the study of the asymmetry of bacterial molecules to the discovery of antimicrobial peptides. Antibiotics and chemotherapy. Vol. 67. no. 3-4. pp. 85-92. http://dx.doi.org/10.37489/0235-2990-2022-67-3-4-85-92

2. Bely, P. A., Lopatukhin, E.Yu., Zaslavskaya, K. Ya., Fedorov, S.V., Zemskov, D. N., & Nigmatova, D. A. (2023). Promomed Rus Limited Liability Company. A new strain is a producer of vancomycin Amycolatopsis japonica. Russian patent No. RU2788348C1 dated 17.01.2023; Issue No. 2.

3. Bliznyak, O. V., & Uranova, V. V. (2023). Current trends in the development of the global pharmaceutical market. Trends in the development of science and education. No. 97-9. pp. 163-167. http://dx.doi.org/10.18411/trnio-05-2023-517

4. Botnariuk, M. V., & Timchenko, T. N. (2022). The Russian pharmaceutical market: the main trends of development and pricing in modern conditions. Problems of Social Hygiene, Health Care and the History of Medicine. 30(2), 198-206. http://dx.doi.org/10.32687/0869-866X-2022-30-2-198-206

5. Borisenko, E.A., & Soldatova, S.Yu. (2018). Pharmacological effect of chamomile components and its use in cosmetics. Collection of materials of the national scientific and practical conference «Biotechnology and products of bioorganic synthesis». pp. 135-140.

6. Venediktova, N. V. (2023). The history of production and prospects for the use of natural and semi-synthetic glycopeptides. Young pharmacy-the potential of the future. pp. 720-724.

7. Vysochanskaya, O.N., Kuleshova, S.I., & Simonova, E.P. (2023). Glycopeptide antibiotics: structural and functional aspects, medical applications and standardization. Bulletin of the Scientific Center for the Examination of medical products. Regulatory research and expertise of medicines. 13(2-1):261-270. http://dx.doi.org/10.30895/1991-2919-2022-447

8. Kovzalov, N. S., Manaeva, A.D., & Nemtseva, N. V. (2023). Non-ribosomal peptides and their application in modern medicine. International Student Scientific Bulletin. No. 2. http://dx.doi.org/10.17513/msnv.21262

9. Kovtun, N. A., Mironov, A.V., Redko, I.A., Titarova, Yu.Yu., Bazarova, M.B., & Boyarintsev V.V. (2023). A two-year study of the antimicrobial activity of cement spacer with vancomycin in vitro. Kremlin medicine. Clinical Bulletin. No. 4. pp. 49-51. http://dx.doi.org/10.48612/cgma/319k-u5t5-agtb

10. Kuleshova, S. I. (2015). Determination of antibiotic activity by diffusion into agar. Bulletin of the Scientific Center for the Examination of medical products. No.3.

11. Lagun, L. V., Kashina, N. A., & Kulvinsky E. A. (2021). Antibacterial activity of vancomycin against methicillin-resistant strains of Staphylococcus Aureus. Clinical microbiology and antimicrobial chemotherapy. vol. 23. no. S1. pp. 24-25.

12. Lopatina, P.A. (2023). The pharmaceutical industry in conditions of economic instability and prospects for its development. Economics and Business: Theory and practice. No.9 (103). http://dx.doi.org/10.24412/2411-0450-2023-9-130-134

13. Marushchak, M.M., & Subbotina T.N. (2023). The impact of sanctions measures on the production of medicines in Russia. Economics and Business: theory and practice. №12-1 (106). http://dx.doi.org/10.24412/2411-0450-2023-12-1-136-138

14. Ziyuan, M., & Kochergin, N.G. (2019). Antimicrobial peptides in the treatment of patients with vulgar acne. Russian Journal of Skin and Venereal Diseases. No.5-6.

15. Muravyeva, V.B., Soboleva, N.I., Makhlis, O.A., Bondarenko, V.O., & Dorozhkin V.I. (2022). Comparative characteristics of agar diffusion methods for determining the activity of tylosin. Problems of veterinary sanitation, hygiene and Ecology. No. 1 (41). pp. 93-98. http://dx.doi.org/10.36871/vet.san.hyg.ecol.202201011

16. Olefir, Yu. V. (2018). The use of the turbidimetric method of analysis for standardization and quality assessment of antibiotics of the aminoglycoside group and medicines based on them. Antibiotics and chemotherapy. Vol. 63. No. 7-8. pp. 62-66.

17. Sakanyan, E. I. (2022). Turbidimetry in standardization and quality control of medicines (using the example of antibiotics of the aminoglycoside group). Abstract for the degree of Candidate of Technical Sciences. pp. 1-23.

18. Semenova, E. N., & Kuleshova, S. I. (2019). Determination of the antimicrobial activity of gentamicin in a cream for external use by the turbidimetric method. Scientific dialogue: Questions of medicine. pp. 15-19. http://dx.doi.org/10.18411/sciencepublic-15-07-2019-05

19. Semenova, E. N., Kuleshova, S. I., & Sakanyan E. I. (2020). Development of a turbidimetric technique for the quantitative determination of antibiotics of the aminoglycoside group in medicinal products for medical use. Antibiotics and chemotherapy. Vol. 65. No. 7-8. pp. 37-41. http://dx.doi.org/10.37489/0235-2990-2020-65-7-8-37-41

20. Semenova, E. N., Sakanyan, E. I., & Kuleshova, S. I. (2017). Comparative characteristics of quantitative determination methods used in the standardization and subsequent assessment of the quality of antibiotics. Bulletin of the Russian Military Medical Academy. No. 3. pp. 140-146.

21. Soldatova, S.Yu., Filatova, G.L., & Kulikovskaya, T.S. (2019). Listeriosis is an emergent infection with foodborne transmission. Bulletin of Nizhnevartovsk State University. No. 2. pp. 110-117.

22. Subbotina, T.N., & Nesuk, P.I. (2023). The activity of pharmaceutical clusters in the context of the geopolitical crisis. Economics and Business: theory and practice. №12-2 (106). http://dx.doi.org/10.24412/2411-0450-2023-12-2-166-169

23. Tarasevich, V. N. (2019). Antibiotics for medical use in the pharmaceutical market of the Russian Federation. Medical and pharmaceutical journal Pulse. vol. 21, No. 11. pp. 101-109. http://dx.doi.org / 10.26787/nydha-2686-6838-2019-21-11-101-109.

24. Halimova, A.A., Orlov, A.S., & Taube, A.A. (2024). Analysis of the localization of biotechnological drug production in Russia, taking into account the origin of active pharmaceutical substances. Bulletin of the Scientific Center for the Examination of medical products. Regulatory research and expertise of medicines. 14(1):53-61. http://dx.doi.org/10.30895/1991-2919-2024-14-1-53-61

25. Shepelin, A. P., & Domotenko L. V. (2019). A disco diffusion method for determining the sensitivity of microorganisms to antibacterial drugs. Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy. No. 4-1. pp. 2-5.

26. Eidelstein, M. V., Kozlov, R. S., Sukhorukova, M. V., Ivanchik, N. V., Skleenova, E. Yu., Timokhova, A.V., & Dehnich, A.V. (2014). Determination of the sensitivity of microorganisms to antimicrobial drugs. Clinical recommendations. Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy. pp. 175-195.

27. Alexander, H. T. & Chu, (1996) Abbott Laboratories, AbbottPark, Il. Process for making vancomycin. United States Patent US 5,574,135. Nov.12,1996.

28. Barreteau, H., Patin, D., Bouhss, A., Blanot, D., Mengin-Lecreulx, D., & Touzé, T. (2020). CbrA Mediates Colicin M Resistance in Escherichia coli through Modification of Undecaprenyl-Phosphate-Linked Peptidoglycan Precursors. J Bacteriol. http://dx.doi.org/10.1128/JB.00436-20

29. Bruniera, F.R., Ferreira, F.M., Saviolli, L.R., Bacci, M.R., Feder, D., da Luz Gonçalves Pedreira, M., Sorgini Peterlini, M.A., Azzalis, L.A., Campos Junqueira, V.B., & Fonseca, F.L. (2015). The use of vancomycin with its therapeutic and adverse effects: a review. Eur Rev Med Pharmacol Sci. 19(4):694-700.

30. Chen, S., Rao, M., Jin, W., Hu, M., Chen, D., Ge, M., Mao, W., & Qian, X. (2024). Metabolomic analysis in Amycolatopsis keratiniphila disrupted the competing ECO0501 pathway for enhancing the accumulation of vancomycin. World J Microbiol Biotechnol. http://dx.doi.org/10.1007/s11274-024-04105-9.

31. Correa, M. G. (2020). Antimicrobial metal-based nanoparticles: A review on their synthesis, types and antimicrobial action. Beilstein journal of nanotechnology. Т. 11. №. 1. С. 1450-1469. http://dx.doi.org/10.3762/bjnano.11.129

32. El-Aziz, H.A., Fathy, M.E., El-Enany, N., Aly, F.A., & Tolba, M.M. (2021). Investigation of some univariate and multivariate spectrophotometric methods for concurrent estimation of Vancomycin and Ciprofloxacin in their laboratory prepared mixture and application to biological fluids. Spectrochim Acta A Mol Biomol Spectrosc. http://dx.doi.org/10.1016/j.saa.2021.119570.

33. Heng, W. L. (2012). From penicillin-streptomycin to amikacin-vancomycin: antibiotic decontamination of cardiovascular homografts in Singapore. PloS one. –Т. 7. №. 12. http://dx.doi.org/10.1371/journal.pone.0051605

34. Jekhmane, S., Derks, M.G.N., Maity, S., Slingerland, C.J., Tehrani, K.H.ME., Medeiros-Silva, J., Charitou, V., Ammerlaan, D., Fetz, C., Consoli, N.A., Cochrane, R.V.K., Matheson, E.J., van der Weijde, M., Elenbaas, B.O.W., Lavore, F., Cox, R., Lorent, J.H., Baldus, M., Künzler, M., Lelli, M., Cochrane, S.A., Martin, N.I., Roos, W.H., Breukink, E., & Weingarth, M. (2024). Host defence peptide plectasin targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism. Nat Microbiol. 9(7):1778-1791. http://dx.doi.org/10.1038/s41564-024-01696-9

35. Jung. H.M., Kim, S.Y., Moon, H.J., Oh, D.K., & Lee, J.K. (2007). Optimization of culture conditions and scale-up to pilot and plant scales for vancomycin production by Amycolatopsis orientalis. Appl Microbiol Biotechnol. 77(4):789-95. http://dx.doi.org/10.1007/s00253-007-1221-4.

36. Li, Q., Montalban-Lopez, M., & Kuipers, O.P. (2018). Increasing the Antimicrobial Activity of Nisin-Based Lantibiotics against Gram-Negative Pathogens. Appl Environ Microbiol. http://dx.doi.org/10.1128/AEM.00052-18.

37. Li, X., Zuo, S., Wang, B., Zhang, K., & Wang, Y. (2022). Antimicrobial Mechanisms and Clinical Application Prospects of Antimicrobial Peptides. Molecules. 27(9):2675. http://dx.doi.org/10.3390/molecules27092675.

38. 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. (2015). A new antibiotic kills pathogens without detectable resistance. Nature. 517(7535):455-9. http://dx.doi.org/10.1038/nature14098

39. Liu, Y., Shuangyang, D., Jianzhong, Sh., & Kui, Zhu. (2019). Nonribosomal antibacterial peptides that target multidrug-resistant bacteria. Natural product reports. Т. 36. №. 4. С. 573-592. http://dx.doi.org/10.1039/C8NP00031J

40. Luo, Y., & Song, Y. (2021). Mechanism of Antimicrobial Peptides: Antimicrobial, Anti-Inflammatory and Antibiofilm Activities. Int J Mol Sci. 22(21):11401. http://dx.doi.org/10.3390/ijms222111401.

41. Teixeira da Trindade, M., Kogawa, A.C., & Nunes Salgado, H. R. (2021). Turbidimetric Method: A Multi-Vantageous Option for Assessing the Potency of Ceftriaxone Sodium in Powder for Injection, Journal of AOAC International, Volume 104, Issue 1, P. 204–210. http://dx.doi.org/10.1093/jaoacint/qsaa085

42. Marschall, E., Cass, R.W., Prasad, K.M., Swarbrick, J.D., McKay, A.I., Payne, J.A.E., Cryle, M.J., & Tailhades, J. (2023). Synthetic ramoplanin analogues are accessible by effective incorporation of arylglycines in solid-phase peptide synthesis. Chem Sci. 15(1):195-203. http://dx.doi.org/10.1039/d3sc01944f.

43. Ned, P.B., Halana, C., Vlaming С., Kotsogianni, I., Arts, M., Willemse, J., Duan, Y., Alexander, F. M., Cochrane, St.A., Schneider, T., & Martin, N.I. (2024). A classic antibiotic reimagined: Rationally designed bacitracin variants exhibit potent activity against vancomycin-resistant pathogens. Proceedings of the National Academy of Sciences. 121, 29. http://dx.doi.org/10.1073/pnas.2315310121

44. Nicolaou, K. C., Nicolaou, K.C., Mitchell, H.J., Jain, N.F., Winssinger, N., Hughes, R., & Bando, T. (1999). Total synthesis of vancomycin. Angewandte Chemie International Edition. Т. 38. №. 1‐2. С. 240-244. http://dx.doi.org/10.1002/(SICI)1521-3773(19990115)38:1/2.

45. Park, J.H., Reviello, R.E., & Loll, P.J. (2024). Crystal structure of vancomycin bound to the resistance determinant D-alanine-D-serine. IUCrJ. 11(2):133-139. http://dx.doi.org/10.1107/S2052252524000289

46. Do Nascimento, P.A., Kogawa, A.C., & Nunes Salgado, H.R. (2020). Turbidimetric Method: A New, Ecological, and Fast Way to Evaluate of Vancomycin Potency, Journal of AOAC International, Volume 103, Issue 6, P. 1582–1587. http://dx.doi.org/10.1093/jaoacint/qsaa068

47. Ponder, C., & Overcash, M. (2010). Cradle-to-gate life cycle inventory of vancomycin hydrochloride. Sci Total Environ. 408(6):1331-7. http://dx.doi.org/10.1016/j.scitotenv.2009.10.057

48. Protić, S., Kaličanin, N., Sencanski, M., Prodanović, O., Milicevic, J., Perovic, V., Paessler, S., Prodanović, R., & Glisic, S. (2023). In Silico and In Vitro Inhibition of SARS-CoV-2 PLpro with Gramicidin D. Int J Mol Sci. 24(3):1955. http://dx.doi.org/10.3390/ijms24031955.

49. Tótoli, E. G., & Salgado, H. R. N. (2013). Development and validation of a rapid turbidimetric assay to determine the potency of ampicillin sodium in powder for injectable solution. Analytical Methods. Т. 5. №. 21. С. 5923-5928. http://dx.doi.org/10.1039/C3AY40847G

50. Trimble, M.J., Mlynárčik, P., Kolář, M., & Hancock, R.E. (2016). Polymyxin: Alternative Mechanisms of Action and Resistance. Cold Spring Harb Perspect Med. 6(10):a025288. http://dx.doi.org/10.1101/cshperspect.a025288.

51. Vila, M. M. D. C., Machado de Oliveira, R., Gonçalves, M.M., & Tubino, M. (2007). Analytical methods for vancomycin determination in biological fluids and in pharmaceuticals. Química Nova. 30. P. 395-399. http://dx.doi.org/10.1590/S0100-40422007000200029

52. Zhu, J., Wang, S., Wang, C., Wang, Z., Luo, G., Li, J., Zhan, Y., Cai, D., & Chen, S. (2023). Microbial synthesis of bacitracin: Recent progress, challenges, and prospects. Synth Syst Biotechnol. 8(2):314-322. http://dx.doi.org/10.1016/j.synbio.2023.03.009.