Cruentaren A, a highly cytotoxic benzolactone from Myxobacteria is a novel selective inhibitor of mitochondrial F₁-ATPases

Abstract 

Cruentaren A, a new antifungal benzolactone produced by the myxobacterium Byssovorax cruenta, proved to be highly cytotoxic against various human cell lines. It inhibited the proliferation of different cancer cell lines including a multidrug-resistant KB line at low nanomolar levels. It arrested human histocytic lymphoma cells (U-937) in G_0/1 phase, but did not trigger an apoptotic process. Studies to uncover the molecular target of cruentaren A showed that the novel compound, despite its structural similarity to the benzolactone enamides apicularen and salicylihalamide, was no V-ATPase inhibitor. In contrast, cruentaren specifically inhibited mitochondrial F_OF₁-ATPases with IC50 values of 15–30nM. Although the exact binding site of cruentaren remains undefined, inhibition was shown to occur by interaction with the catalytic F₁ domain. Since mitochondrial ATPases play a crucial role in the pathophysiology of several human disorders including cancer, cruentaren or synthetic derivatives thereof could form the basis of future therapeutic strategies.

Keywords: Cruentaren, Myxobacteria, Benzolactone class, Cytotoxic activity, Mitochondrial F1-ATPase inhibitor