Metal Chelating Antibiotic

New antibiotic therapies are in dire need to combat increasing antibiotic resistance. Small molecules produced by microorganisms, or natural products, are a rich source of antibiotics, because the activities of these molecules have been optimized over millions of years of evolution. However, many natural products are currently underexplored in antimicrobial therapy, in part due to a lack of understanding of the mechanisms of action of these molecules.

The Li Group in our Biological Division recently published in the Proceedings of the National Academy of Sciences of the United States of America on the action of a unique class of natural products, the dithiolopyrrolones, DTPs. DTPs contain a redox-active cyclic disulfide and exhibit broad-spectrum activities against multidrug-resistant pathogens.

The group found that the DTP holomycin acts as a prodrug and the reduced form of holomycin chelate metal ions with high affinity. By chelating essential metals, especially zinc, holomycin limits zinc availability in the cell and removes zinc from zinc metalloenzymes, thereby inactivating these enzymes, which can have manifold effects on bacterial growth.

This work connects the unique chemistry of DTPs with the potent biological activity of these molecules. The Li Group is studying the in vivo activity and therapeutic potential of these antibiotics.

This work was also highlighted in C&EN news