Irene Wagner-Döbler, Asfandyar Sikandar, Jannik Donner, Jennifer Herrmann, Michael Reck, Chengzhang Fu, Nestor Zaburannyi, Jesko Koehnke, Rolf Müller, and Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124Braunschweig, Germany.
The natural product carolacton is a macrolide keto-carboxylic acid produced by the myxobacterium Sorangium cellulosum, and was originally described as an antibacterial compound. Here we show that carolacton targets FolD, a key enzyme from the folate-dependent C1 metabolism. We characterize the interaction between bacterial FolD and carolacton biophysically, structurally and biochemically. Carolacton binds FolD with nanomolar affinity, and the crystal structure of the FolD–carolacton complex reveals the mode of binding. We show that the human FolD orthologs, MTHFD1 and MTHFD2, are also inhibited in the low nM range, and that micromolar concentrations of carolacton inhibit the growth of cancer cell lines. As mitochondrial MTHFD2 is known to be upregulated in cancer cells, it may be possible to use carolacton as an inhibitor tool compound to assess MTHFD2 as an anti-cancer target., The mechanisms behind the antibacterial activity of the natural product carolacton are unknown. Here, the authors show that carolacton is a potent inhibitor of FolD/MTHFD enzymes (involved in folate-dependent C1 metabolism in bacteria and humans) and inhibits the growth of cancer cell lines