Kendomycin is a small-molecule natural
product that has gained
significant attention due to reported cytotoxicity against pathogenic
bacteria and fungi as well as a number of cancer cell lines. Despite
significant biomedical interest and attempts to reveal its mechanism
of action, the cellular target of kendomycin remains disputed. Herein
it is shown that kendomycin induces cellular responses indicative
of cation stress comparable to the effects of established iron chelators.
Furthermore, addition of excess iron and copper attenuated kendomycin
cytotoxicity in bacteria, yeast, and mammalian cells. Finally, NMR
analysis demonstrated a direct interaction with cations, corroborating
a close link between the observed kendomycin polypharmacology across
different species and modulation of iron and/or copper levels.