Biotransformation on nitazoxanide by filamentous fungi - a microbial model to mammalian metabolism

Julia Medeiros  Sorrentino; Rafaela Martins Sponchiado; Fábio Souza Barbosa; Joanna Wittckind Manoel; Ilana Saute Glock  Slub; Victoria Raabe; Tiago Franco de Oliveira; Martin Steppe

doi:10.22456/2527-2616.145722

Authors

Julia Medeiros Sorrentino Programa de Pós-Graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul https://orcid.org/0000-0003-0803-8225
Rafaela Martins Sponchiado Programa de Pós-Graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul https://orcid.org/0000-0003-4824-2247
Fábio Souza Barbosa Programa de Pós-Graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul https://orcid.org/0000-0001-6796-1437
Joanna Wittckind Manoel Programa de Pós-Graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul https://orcid.org/0000-0002-1239-9544
Ilana Saute Glock Slub Faculdade de Farmácia - Universidade Federal do Rio Grande do Sul
Victoria Raabe Faculdade de Farmácia - Universidade Federal do Rio Grande do Sul
Tiago Franco de Oliveira Programa de PósGraduação em Ciências da Saúde - Universidade Federal de Ciências da Saúde de Porto Alegre https://orcid.org/0000-0003-2594-8415
Martin Steppe Programa de Pós-Graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul https://orcid.org/0000-0002-2053-6350

DOI:

https://doi.org/10.22456/2527-2616.145722

Keywords:

nitazoxanide, biotransformation, Aspergillus niger, Cunninghamella elegans, metabolites

Abstract

Filamentous fungi exhibit a complex morphology and can display various shapes depending on the species and environment. These characteristics serve as advantages in biotransformation studies by allowing substances to undergo processes that lead to the production of both existing metabolites and new compounds with potential pharmacological activity. In this regard, the biotransformation of drugs using microorganisms emerges as an economical and ecologically viable strategy for modifying the structures of biologically active compounds, studying the metabolism of molecules, and eliminating or reducing their toxicity. Therefore, the objective of this study was to investigate the biotransformation capacity of the drug nitazoxanide by the endophytic fungi Aspergillus niger ATCC 9029 and Cunninghamella elegans ATCC 9245. High-performance liquid chromatography was employed to monitor metabolite formation, while ultra-high-performance liquid chromatography coupled with sequential mass spectrometry (UHPLC-QTOF/MS) was utilized to identify these metabolites. After an incubation period of 240 hours, nitazoxanide was transformed into two metabolites by C. elegans. A. niger demonstrated a consumption rate of 94.17% for nitazoxanide, with two additional metabolites identified. This study highlights the potential of using fungi both as a model for metabolism and as a means of producing metabolites on a larger scale, while also identifying a new and significant area of application for the biotransformation approaches involving filamentous fungi.

Downloads

Download data is not yet available.

References

Khan MF, Hof C, Niemcová P, Murphy CD. Recent advances in fungal xenobiotic metabolism: enzymes and applications. World J Microbiol Biotechnol [Internet]. 2023 Nov 2;39(11):296. Available from: https://link.springer.com/10.1007/s11274-023-03737-7

Ibrahim ARS, Mansour MK, Ahmed MMA, Ulber R, Zayed A. Metabolism of natural and synthetic bioactive compounds in Cunninghamella fungi and their applications in drug discovery. Bioorg Chem [Internet]. 2023 Nov 1;140:106801. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0045206823004625

Rossingnol JF, Cavier R. Synthesis and antiparasitic activity of 2-benzoamino nitrothiazoles. Chem Abstr. 1975;83:28216.

Broekhuysen J, Stockis A, Lins RL, Graeve J De, Rossignol JF. Nitazoxanide: pharmacokinetics and metabolism in man. Int Journal of Clinical Pharmacology and Therapeutics [Internet]. 2000 Aug 1;38(08):387–94. Available from: http://www.dustri.com/article_response_page.html?artId=6194&doi=10.5414/CPP38387&L=0

Gekonge B, Bardin MC, Montaner LJ. Short Communication: Nitazoxanide Inhibits HIV Viral Replication in Monocyte-Derived Macrophages. AIDS Res Hum Retroviruses [Internet]. 2015 Feb;31(2):237–41. Available from: http://www.liebertpub.com/doi/10.1089/aid.2014.0015

Oesch F, Fabian E, Landsiedel R. Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models. Arch Toxicol [Internet]. 2018 Aug 18;92(8):2411–56. Available from: http://link.springer.com/10.1007/s00204-018-2232-x

Guo L, Dial S, Shi L, Branham W, Liu J, Fang JL, et al. Similarities and differences in the expression of drug-metabolizing enzymes between human hepatic cell lines and primary human hepatocytes. Drug Metabolism and Disposition. 2011;39(3).

Brandon EFA, Raap CD, Meijerman I, Beijnen JH, Schellens JHM. An update on in vitro test methods in human hepatic drug biotransformation research: Pros and cons. Toxicol Appl Pharmacol. 2003;189(3).

Gonçalves MD, Tomiotto-Pellissier F, de Matos RLN, Assolini JP, da Silva Bortoleti BT, Concato VM, et al. Recent Advances in Biotransformation by Cunninghamella Species. Curr Drug Metab. 2021 Nov 26;22(13):1035–64.

Tembeni B, Idowu OE, Benrkia R, Boutahiri S, Olatunji OJ. Biotransformation of selected secondary metabolites by Alternaria species and the pharmaceutical, food and agricultural application of biotransformation products. Nat Prod Bioprospect. 2024 Dec 19;14(1):46.

Lustosa KRMD, Menegatti R, Braga RC, Lião LM, de Oliveira V. Microbial β-glycosylation of entacapone by Cunninghamella echinulata ATCC 9245. J Biosci Bioeng [Internet]. 2012 May;113(5):611–3. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1389172312000254

Sponchiado R, Sorrentino JM, Olegário N, Oliveira SS, Cordenonsi LM, Silveira GP, et al. Microbial transformation of ambrisentan to its glycosides by Cunninghamella elegans. Biomedical Chromatography [Internet]. 2019 Jun 15;33(6):1–7. Available from: https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/bmc.4496

Murzyn A, Popiół J, Gunia-Krzyżak A, Żelaszczyk D, Dąbrówka B, Koczurkiewicz-Adamczyk P, et al. Biotransformation of oxybenzone and 3-(4-methylbenzylidene)camphor in Cunninghamella species: Potential for environmental clean-up of widely used sunscreen agents. J Hazard Mater. 2025 Jun;489:137544.

Zheng C chao, Gao L, Sun H, Zhao XY, Gao Z qing, Liu J, et al. Advancements in enzymatic reaction-mediated microbial transformation. Heliyon. 2024 Oct;10(19):e38187