Target Discovery and Application of Bioactive Compounds: the Natural Product Vibralactone and Other Beta-lactones

Activity based protein profiling (ABPP) is a novel strategy that allows the identification of enzyme targets of small molecules, like natural products and their derivatives, in biological systems. The natural product vibralactone targeted two isoforms of the virulence associated protease ClpP in L. monocytogenes. In vitro studies using ABPP, electron microscopy, and x-ray crystallography revealed valuable insights into the field of ClpP hetero-complexes. Moreover, new ?-lactones were synthesized, which specifically inhibit ClpP and were used as virulence inhibitors in S. aureus and as antibiotics in M. tuberculosis. In addition, the targets of the natural product vibralactone were identified in eukaryotic cells and the non-reactivity against the eukaryotic proteasome aided in identifying the important functional groups of a potent inhibitor.