Abstract
Antibiotics are some of the most widely used drugs. Their release in the environment is of great concern since their consumption is a major factor for antibiotic resistance, one of the most important threats to human health. Their occurrence and fate in agricultural systems have been extensively investigated in recent years. Yet whilst their biotic and abiotic degradation pathways have been thoroughly researched, their biotransformation pathways in plants are less understood, such as in case of trimethoprim. Although trimethoprim has been reported in the environment, its fate in higher plants still remains unknown. A bench-scale experiment was performed and 30 trimethoprim metabolites were identified in lettuce (Lactuca sativa L.), of which 5 belong to phase I and 25 to phase II. Data mining yielded a list of 1018 ions as possible metabolite candidates, which was filtered to a final list of 87 candidates. Molecular structures were assigned for 19 compounds, including 14 TMP metabolites reported for the first time. Alongside well-known biotransformation pathways in plants, additional novel pathways were suggested, namely, conjugation with sesquiterpene lactones, and abscisic acid as a part of phase II of plant metabolism. The results obtained offer insight into the variety of phase II conjugates and may serve as a guideline for studying the metabolization of other chemicals that share a similar molecular structure or functional groups with trimethoprim. Finally, the toxicity and potential contribution of the identified metabolites to the selective pressure on antibiotic resistance genes and bacterial communities via residual antimicrobial activity were evaluated.
Highlights
Antibiotics (ABs) are one of the most widely used categories of pharmaceuticals [1]
The applicability of the Orbitrap Mass Spectrometer has been already confirmed [31]; Bade et al [34] observed slightly better performances of Orbitrap compared with QTOF, the non-target screening results were very similar. In light of these considerations, the main aim of this study is to identify the TMP metabolites in lettuce (Lactuca sativa L.) as a model plant, using high-resolution LC-HRMSn spectra with an emphasis on the unknown phase II metabolites, and to suggest the major biotransformation reactions
30 TMP metabolites were identified with a mass error lower than 4 ppm, 19 with identification confidence levels [40] 1 and 3 (Table 1), and 11 with a level of 4 or 5 (Table 2) illustrating the suitability of the applied method for the identification and structural elucidation of unknown molecules
Summary
Antibiotics (ABs) are one of the most widely used categories of pharmaceuticals [1]. ABs are used extensively in human and veterinary medicine, including aquaculture, to prevent or treat microbial infections [2]. AB consumption is a primary driver of AB resistance, the ability of microbes to evolve and withstand the effects of ABs, which is considered one of the greatest threats to human health worldwide [3, 4]. Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 812 37 Bratislava, Slovakia production are increasing antibiotic consumption around the world [1], mostly through misuse and overuse of ABs in agriculture [5]. The COVID-19 pandemic has contributed to overuse in human medication, too, e.g. 72% of COVID-19 patients in the USA received ABs even though they were not clinically indicated [6]. There is a continual discharge of ABs into ecosystems due to animal and human application and AB manufacturing plant [7] and hospital [8] discharges
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