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1. INTRODUCTION Several contaminants of emerging concern (CECs), including macrolide antibiotics, enter aquatic compartments, such as surface water, groundwater and even drinking water at concentrations ranging from a few ng L-1 to several μg L-1 (1). As conventional wastewater treatment plants are not designed to remove complex organic compounds, such as pharmaceuticals, their metabolites, and potential transformation products, CECs enter the environment and can have adverse effects on living organisms and plants. Among the different classes of pharmaceuticals found in the environment, special attention has been paid to macrolide antibiotics, such as azithromycin, clarithromycin, and erythromycin, which are the most discussed because of their potential to contribute to the development of antimicrobial resistance (AMR) (2). To date, most studies have focused on the parent compounds, and little attention has been paid to the intermediates/metabolites they produce. Drugs excreted by humans and/or animals may be present in wastewater treatment plant effluents at higher concentrations than in their respective influents, because they are excreted as conjugates, which are broken down in wastewater treatment plants and generally metabolized during biological treatment, increasing the concentration of the parent compound at the output of the treatment plants. Since there is a lack of data on the chronic toxicity of such compounds, and ecotoxicological data for mixtures of drugs, their metabolites, and transformation products, it is of great importance to study their potential degradation pathways. 2. MATERIALS AND METHODS 2.1. Materials The macrolide antibiotic azithromycin was used in this study. 2.2. Methods Using BioTransformer (3), a web server software available at www.biotransformer.ca, the aerobic and anaerobic microbial degradation of azithromycin in the environment was performed in soil and water and the predicted biotransformation metabolites were compared with the predicted metabolites of azithromycin in humans. 3. RESULTS AND DISCUSSION 3.1. Predicted aerobic and anaerobic microbial degradation of azithromycin in the environment. Several aerobic and anaerobic intermediates/metabolites were predicted for the azithromycin molecule (Table 1, Figure 1) most of which are formed by oxidation of the hydroxyl group at positions C2’ (1), C11 (2), C4’’ (3), or after hydrolysis of the glycoside bonds and removal of the sugar moieties, by oxidation of the formed hydroxyl groups to ketone moieties, C3 (8), C5 (7), C1’ (4) and C1” (11) or by reduction of formed ketones to the secondary hydroxyl group at positions C3 (10), C5 (5), C1’ (6) and C1” (9). In addition to the oxidation/reduction reactions, hydrolysis of the lactone bond was also observed, 13: C1(=O)–OH and C13–OH, as well as the formation of C3” (12) metabolites after O-dealkylation. 3.2. Predicted metabolism of azithromycin in humans The predicted metabolites formed by CYP enzymes in humans are similar to the predicted oxidative/reductive degradation products in the environment, but also include N–dealkylated metabolites. In human metabolism, the degradation of the lactone ring was not predicted. Conjugation with glucuronic acid at positions C2’ (1), C6 (2) C11 (3), C12 (4), C4” (5) and the charged glucuronide R–N+(CH3)2–Gluc (6) were predicted (Figure 2). Figure 1. Predicted environmental aerobic and anaerobic microbial degradation of azithromycin in soil and water (www.biotransformer.ca) Figure 2. Predicted conjugation metabolites of azithromycin with glucuronic acid (www.biotransformer.ca) Table 1. List of predicted microbial aerobic and anaerobic metabolites of azithromycin in the environment. 4. CONCLUSION The predicted biotransformation of azithromycin either by microbial degradation in the environment or by metabolism in humans by CYP enzymes or glucuronic acid conjugation generates many metabolites that may increase the environmental toxicity of this antibiotic and its contribution to antimicrobial resistance (AMR). 5. REFERENCES 1. Barbosa, M. O., et al., Occurrence and removal of organic micropollutants: An overview of the watch list of EU Decision 2015/495. Water Research, 2016, 94: 257–279. 2. Kümmerer, K., Antibiotics in the aquatic environment—a review—part I. Chemosphere, 2009, 75(4): 417–434. 3. Djoumbou-Feunang, Y., et al., BioTransformer: A comprehensive computational tool for small molecule metabolism prediction and metabolite identification. Journal Cheminformatics 2019, 11(2): 1-25. |
