Bacteria produce many small molecules that possess unique structures and potent antimicrobial activity.  It is often unclear how these molecules impart their activity. I will discuss our work on understanding the mode of action for the broad-spectrum, dithiolopyrrolone antibiotics. We showed that this family of natural products inhibits metal-dependent enzymes in cells via metal-ion chelation. The cyclic ene-disulfide of the dithiolopyrrolone exhibits unusual redox chemistry and is essential for activity. I will also describe our recent efforts on elucidating the mode of action of the natural product thiomarinol A, a hybrid antibiotic that combines the dithiolopyrrolone and a close analog of mupirocin, the latter of which is used to treat methicillin-resistant <i>Staphylococcus aureus</i>. Thiomarinol A remains effective against high-level mupirocin-resistant <i>S. aureus</i>. Our findings could help discover and design antibiotics that can avoid or overcome resistance.

Mighty chemistry of bacterial small molecules as antibiotics

ACS Fall 2021

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