Ambigols Uncouple Oxidative Phosphorylation In Vitro

Ambigols are natural products produced by the cyanobacterium Symphyonema bifilamentata. Especially ambigols A and C have a broad bioactivity spectrum. Therefore, ambigols have been discussed as promising compounds, e.g., for the development of new antibiotics. However, their mode of action is still unknown, although first steps have been undertaken toward its elucidation. Here, we show that ambigols A and C are uncouplers of oxidative phosphorylation. They dissipate the mitochondrial membrane potential and increase the oxygen consumption rate of HeLa cells. A further target is the membrane potential of Gram-negative bacteria. The disturbance of the electrochemical membrane potential in prokaryotic and eukaryotic cells shows the unspecific effects of typical uncouplers. These results provide a basis for a deeper understanding of the broad bioactivity spectrum of the ambigols, challenging the future development of ambigol-based compounds for clinical application.