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Evaluation of microbiological and chemical models for the study of (bio)transformations of the antibiotic monensin A

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Author(s):
Bruno Alves Rocha
Total Authors: 1
Document type: Doctoral Thesis
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
Defense date:
Examining board members:
Marilda das Dores de Assis; Antonio Eduardo Miller Crotti; Niege Araçari Jacometti Cardoso Furtado; Cintia Duarte de Freitas Milagre; Katia Jorge Ciuffi Pires
Advisor: Marilda das Dores de Assis; Anderson Rodrigo Moraes de Oliveira
Abstract

This study used model systems to investigate monensin A metabolism. More specifically, this work employed three strategies: (i) use of biomimetic systems, involving metalloporphyrins and salen complexes, to catalyze monensin A oxidation by different oxidants in distinct reaction media; (ii) application of different fungal strains to conduct biotransformation studies of this antibiotic; and (iii) use of rat and human liver microsomes as a cytochrome P450 model to monitor the in vitro metabolism of monensin A and compare the products with the metabolites generated in in vivo studies reported in the literature. Studies involving chemical catalysts showed that product formation depended on the choice of reaction medium and oxidant. Monensin A biotransformation studies employing fungi revealed that Aspergillus awamori, Beauveria bassianna, Cunninghamella echinulata, Cunninghamella elegans, Fusarium oxysporum, Marine M61, Mucor rouxii, and Penicillium brevicompactum successfully biotransformed the drug under the employed conditions. Liver microsomes also effectively transformed the target compound. Spectrometric analysis of the evaluated models attested to the formation of three main metabolites: (i) 3-O-demethyl monensin A, (ii) 12-hydroxy monensin A, and (iii) 12-hydroxy-3-O-demethyl-monensin A as the main monensin A derivatives. The products were identified by tandem mass spectrometry as well as by comparison with standards obtained in other studies. Taken together, the results demonstrated that the models studied herein could help to predict monensin A metabolismthey produced the main metabolites obtained in in vivo studies. Toxicity tests performed on mitochondria and antimicrobial assays revealed that the metabolites 3-O-demethyl-monensin A and 12-hydroxy-monensin A isolated from the reactions that employed chemical catalysts were less active or inactive as compared with monensin A. Therefore, it was possible to infer that monensin A metabolism is a classical detoxification pathway that generates polar molecules. The transport of such cationic molecules through the membrane is more difficult, decreasing their biological properties and facilitating their elimination. (AU)

FAPESP's process: 11/05800-0 - Evaluation of Microbiological and Chemical Models for the Study of Bio(transformations) of Antibiotic Monensin A
Grantee:Bruno Alves Rocha
Support type: Scholarships in Brazil - Doctorate