Divin is a recently discovered, broad-spectrum small molecule antibiotic that inhibits bacterial cell division by preventing the localization of division machinery to the division plane and impeding peptidoglycan remodeling. In addition to its bacteriostatic activity against rapidly dividing bacteria, divin is a potent chemotherapeutic agent for treating biofilms. Recent biochemical and molecular characterization of the mechanism of action of divin demonstrates that it is an intracellular metal chelator that selectively disrupts bacterial iron homeostasis in vivo and inhibits late stages of bacterial cytokinesis. Consistent with its chelation properties, divin-treated bacterial cells have low levels of intracellular iron and activate global iron-starvation response. Excess iron antagonizes the biological activity of divin in vivo and overexpression of iron transporters reduces bacterial sensitivity to divin. This talk characterizes the chemical, biochemical, and cell biological activity of this family of small molecules, builds the first biochemical connection between metal chelators and bacterial cell division, and provides insight into new classes of antibiotics that target bacteria by sequestering essential metal ions.

Exploring the mechanism of small molecule metal ion chelators as chemotherapeutic agents against pathogenic bacteria

249th National Meeting (2015)

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