| Summary: | Carvotacetones (<b>1–7</b>) isolated from <i>Sphaeranthus africanus</i> were screened for their antimycobacterial and efflux pump (EP) inhibitory potential against the mycobacterial model strains <i>Mycobacterium smegmatis</i> mc<sup>2</sup> 155, <i>Mycobacterium aurum</i> ATCC 23366, and <i>Mycobacterium bovis</i> BCG ATCC 35734. The minimum inhibitory concentrations (MICs) of the carvotacetones were detected through high-throughput spot culture growth inhibition (HT-SPOTi) and microbroth dilution assays. In order to assess the potential of the compounds <b>1</b> and <b>6</b> to accumulate ethidium bromide (EtBr) in <i>M. smegmatis</i> and <i>M. aurum</i>, a microtiter plate-based fluorometric assay was used to determine efflux activity. Compounds <b>1</b> and <b>6</b> were analyzed for their modulating effects on the MIC of EtBr and the antibiotic rifampicin (RIF) against <i>M. smegmatis</i>. Carvotacetones <b>1</b> and <b>6</b> had potent antibacterial effects on <i>M. aurum</i> and <i>M. bovis</i> BCG (MIC ≤ 31.25 mg/L) and could successfully enhance EtBr activity against <i>M. smegmatis</i>. Compound <b>1</b> appeared as the most efficient agent for impairing the efflux mechanism in <i>M. smegmatis</i>. Both compounds <b>1</b> and <b>6</b> were highly effective against <i>M. aurum</i> and <i>M. bovis</i> BCG. In particular, compound <b>1</b> was identified as a valuable candidate for inhibiting mycobacterial efflux mechanisms and as a promising adjuvant in the therapy of tuberculosis or other non-tubercular mycobacterial infections.
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