Antimycobacterial activity in a single-cell infection assay of ellagitannins from Combretum aculeatum and their bioavailable metabolites.

The water decoction of Combretum aculeatum aerial parts is traditionally used in Senegal to treat tuberculosis (TB). The extract shows significant antimycobacterial activity in a validated single-cell infection assay. The main aim of this study was to identify the antimycobacterial compounds in the water decoction of Combretum aculeatum. Since the traditional preparations are used orally, a bioactivity assessment of the possible bioavailable human metabolites was also performed. The Combretum aculeatum water decoction extract was first fractionated by flash chromatography. The fractions were submitted to an antibiotic assay against Mycobacterium marinum and to a single-cell infection assay involving Acanthamoeba castellanii as a host. Using these approaches, it was possible to correlate the antimycobacterial activity with two zones of the chromatogram. In parallel with this liquid chromatography (LC)-based activity profiling, high-resolution mass spectrometry (UHPLC-HRMS/MS) revealed the presence of ellagitannin (Et) derivatives in the active zones of the chromatogram. Isolation of the active compounds was performed by preparative chromatography. The structures of the isolated compounds were elucidated by nuclear magnetic resonance (NMR). Additionally, the main human metabolites of commercially available Ets were biologically evaluated in a similar manner. The in vitro bioassay-guided isolation of the Combretum aculeatum water extract led to the identification of three Ets (1-3) and ellagic acid (4). The major compounds 2 and 3 (α- and β-punicalagin, respectively), exhibited anti-infective activity with an IC The observed antimycobacterial properties of the traditional water decoction of Combretum aculeatum might be related to the activity of Ets derivatives (1-3) and their metabolites, such as ellagic acid (4) and urolithin D (7). Despite the relatively weak activity of these metabolites, the high consumption of tannins achieved by taking the usual traditional decoction doses should lead to an important increase in the plasmatic concentrations of these active and bioavailable metabolites. These results support to some extent the traditional use of Combretum aculeatum to treat tuberculosis.

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