Biological evaluation and spectral characterization of a novel tetracenomycin X congener

The aromatic polyketide tetracenomycin X (TcmX) was recently found to be a potent inhibitor of protein synthesis; its binding site is located in a unique locus within the tunnel of the large ribosomal subunit. The distinct mode of action makes this relatively narrow class of aromatic polyketides promising for drug development in the quest to prevent the spread of drug-resistant pathogens. Here we report the isolation and structure elucidation of a novel natural tetracenomycin X congener – 6-hydroxytetraceonomycin X (6-OH-TcmX). In contrast to TcmX, 6-OH-TcmX exhibited lower antimicrobial and cytotoxic activity, but comparable in vitro protein synthesis inhibition ability. A survey on spectral properties of tetracenomycins revealed profound differences in both UV-absorption and fluorescence spectra between TcmX and 6-OH-TcmX, suggesting a significant influence of 6-hydroxylation on the tetracenomycin X chromophore. Nonetheless, characteristic spectral properties of tetracenomycins make them suitable candidates for semi-synthetic drug development (e.g., for targeted delivery, chemical biology, or cell imaging). [Display omitted] •Hydroxylated tetracenomycin X is produced by the Amycolatopsis sp. A23 strain.•6-Hydroxylation reduces both antimicrobial and cytotoxic activity of tetracenomycin X.•6-Hydroxylation significantly alters the tetracenomycin X chromophore.•UV–Vis spectra of tetracenomycins are dependent on solvent and pH.•Activity is impaired, but not due to lower protein synthesis inhibition ability.