Biotransformation of Metronidazole by Cunninghamella elegans ATCC 9245

Julia Medeiros Sorrentino; Rafaela Martins Sponchiado; Natália Olegário dos Santos; Sendy Salles Oliveira; Karina Galle; Cassia Virginia Garcia; Alexandre Meneghello Fuentefria; Martin Steppe

doi:10.22456/2527-2616.94032

Authors

Julia Medeiros Sorrentino Programa de Pós-graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul
Rafaela Martins Sponchiado Programa de Pós-graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul
Natália Olegário dos Santos Faculdade de Farmácia - Universidade Federal do Rio Grande do Sul
Sendy Salles Oliveira Faculdade de Farmácia - Universidade Federal do Rio Grande do Sul
Karina Galle Faculdade de Farmácia - Universidade Federal do Rio Grande do Sul
Cassia Virginia Garcia Programa de Pós-graduação em Ciências Farmacêuticas - Faculdade de Farmácia - Universidade Federal do Rio Grande do Sul
Alexandre Meneghello Fuentefria Programa de Pós-graduação em Ciências Farmacêuticas - Faculdade de Farmácia - Universidade Federal do Rio Grande do Sul
Martin Steppe Programa de Pós-graduação em Ciências Farmacêuticas - Faculdade de Farmácia - Universidade Federal do Rio Grande do Sul

DOI:

https://doi.org/10.22456/2527-2616.94032

Keywords:

biotransformation, HPLC, metabolites, metronidazole

Abstract

Drug biotransformation studies appear as an alternative to pharmacological studies of metabolites, development of new drug candidates with reduced investment as well as the most efficient production of chemical structures involves and drug quality control studies. A wide range of reactions in biotransformations process is catalyzed by microorganisms. Fungi can be considered as a promising source of new biotransformation reactions. The aim of this study was to evaluate the capacity of metronidazole biotransformation through the filamentous fungus Cunninghamella elegans ATCC 9245. The monitoring of metabolite formation was performed by high-performance liquid chromatography (HPLC) coupled to ultraviolet (UV) spectrophotometry. The results of the biotransformation of metronidazole showed drug consumption in culture and the formation of four new chromatographic peaks of chemical structures not elucidated. The method showed it became linear over 10-70 μg/mL (r = 0.999953). Accuracy, precision and stability studies agree with international guidelines. Results are consistent in accordance with the principles of green chemistry as the experimental conditions had a low environmental impact, and few solvents use.

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References

Srisilam K, Veeresham C. Biotransformation of drugs by microbial cultures for predicting mammalian drug metabolism. Biotechnol Adv. 2003;21(1):3–39.

Rydevik A. Drug Metabolites Formed by Cunninghamella Fungi. 2014.

Pollard DJ, Woodley JM. Biocatalysis for pharmaceutical intermediates: the future is now. Trends Biotechnol. 2007;25(2):66–73.

Quinn L, Dempsey R, Casey E, Kane A, Murphy CD. Production of drug metabolites by immobilised Cunninghamella elegans: from screening to scale up. J Ind Microbiol Biotechnol [Internet]. 2015;42(5):799–806.

Barth T, Conti R, Pupo MT, Okano LT, Bonato PS. Chiral HPLC analysis of donepezil, 5-O-desmethyl donepezil and 6-O-desmethyl donepezil in culture medium: Application to fungal biotransformation studies. Anal Bioanal Chem. 2012;404(1):257–66.

de Paula NC, Araujo Cordeiro KCF, de Melo Souza PL, Nogueira DF, da Silva e Sousa DB, Costa MB, et al. Biosynthesis of human diazepam and clonazepam metabolites. Bioorg Med Chem Lett [Internet]. 2015;25(5):1026–9.

Baydoun E, Smith C, Wahab A-, Khan MSA, Ahmad MS, Farran D, et al. Microbial transformation of oxandrolone with Macrophomina phaseolina and Cunninghamella blakesleeana. Steroids [Internet]. 2015;102(June):39–45.

Williams AJ, Deck J, Freeman JP, Paul Chiarelli M, Adjei MD, Heinze TM, et al. Biotransformation of flumequine by the fungus Cunninghamella elegans. Chemosphere. 2007;67(2):240–3.

Keum YS, Lee YH, Jeong-Han K. Metabolism of methoxychlor by cunninghamella elegans ATCC 36112. J Agric Food Chem. 2009;57(17):7931–7.

Smith R V., Rosazza JP. Microbial models of mammalian metabolism. Aromatic hydroxylation. Arch Biochem Biophys. 1974;161(2):551–8.

Parshikov I a., Sutherland JB. Microbial transformations of antimicrobial quinolones and related drugs. J Ind Microbiol Biotechnol. 2012;39(12):1731–40.

Asha S, Vidyathi M. Cunninghamella – A microbial model for drug metabolism studies – A review. Biotechnol Adv [Internet]. 2009 Jan;27(1):16–29.

Pearce CM, Lushnikova M V. Microbiological production of omeprazole metabolites by Cunninghamella elegans. J Mol Catal B Enzym. 2006;41(3–4):87–91.

Jensen C, Gugler R. Single- and multiple-dose metronidazole. 1983;481–7.

Jeelani G, Nozaki T. Entamoeba thiol-based redox metabolism: A potential target for drug development. Mol Biochem Parasitol [Internet]. 2016;206(1–2):39–45.

Keefe JPO, Troc KA, Thompson KD. Activity of Metronidazole and its Hydroxy and Acid Metabolites Against Clinical Isolates of Anaerobic Bacteria. 1982;22(3):426–30.

Jesus RS. Avaliação da formação de biofilme de fungos emergentes e sua susceptibilidade a antifungicos na forma livre e nanocapsulada. [Porto Alegre]: Universidade Federal do Rio Grande do Sul; 2013.

FDA. Guidance for Industry: Bioanalytical Method Validation. U. S. Department of Health and Human Services. Rockville, MD; 2018.

Hegazy MEF, Mohamed TA, ElShamy AI, Mohamed AEHH, Mahalel UA, Reda EH, et al. Microbial biotransformation as a tool for drug development based on natural products from mevalonic acid pathway: A review. J Adv Res [Internet]. 2015;6(1):17–33.

Murphy CD. Drug metabolism in microorganisms. Biotechnol Lett [Internet]. 2015 Jan;37(1):19–28.

Gurram SP, Kollu NR, Sivadevuni G, Solipuram MR. Biotransformation of albendazole by Cunninghamella blakesleeana: Influence of incubation time, media, vitamins and solvents. Iran J Biotechnol. 2009;7(4):205– 15.

Sponchiado R, Sorrentino JM, Olegário N, Oliveira SS, Cordenonsi LM, Silveira GP, et al. Microbial transformation of ambrisentan to its glycosides by Cunninghamella elegans. Biomed Chromatogr. 2019;33(6):1–7.

Murphy CD. Drug metabolism in microorganisms. Biotechnol Lett. 2015;37(1):19–28.

BRASIL M das S, ANVISA AN de VS. Resolução - RDC No 27, de 17 de mao de 2012. Dispõe sobre os requisitos mínimos para validação de métodos bioanalíticos empregados em estudos com fins de registro e pósregistro de medicamentos. [Internet]. Diário Oficial da União. Brasília; 2012.