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Biological Chemistry

Mode of action for unusual antibiotics found

Dithiolopyrrolones chelate metal ions, inhibiting cellular metalloenzymes

by Stu Borman
February 27, 2017 | APPEARED IN VOLUME 95, ISSUE 9

Credit: Adapted from PNAS
Holomycin’s mechanism of action is metal chelation and removal of metals such as Zn2+ from some metalloenzymes.

Dithiolopyrrolones (DTPs) are disulfide-containing natural products with broad-spectrum antimicrobial activity. Studies have shown that DTPs inhibit several essential cellular processes, but their molecular mechanism has remained elusive. Bo Li of the University of North Carolina, Chapel Hill, and coworkers now find that a DTP called holomycin exerts its antibiotic activity by sequestering intracellular metal ions, particularly Zn2+ (Proc. Natl. Acad. Sci. USA 2017, DOI: 10.1073/pnas.1612810114). This metal chelation activity inhibits some metalloenzymes—potentially interfering with cellular glucose utilization, RNA synthesis, and respiration—and disrupts cells’ internal metal balance. The researchers believe holomycin’s mechanism will prove valid for other DTPs. But they note that it is nevertheless a unique antibiotic mode of action, making DTPs potentially useful for treating multi-drug-resistant bacterial infections. After holomycin enters cells, its cyclic disulfide is reduced by an unknown mechanism, and the reduced holomycin is the species that actually chelates metals. Holomycin is moderately toxic, so it may need to be modified to reduce toxicity for possible future antibiotic use. The researchers now plan to “investigate the specificity of DTPs for metalloenzymes in bacterial and human proteomes and develop ways to improve target selectivity,” Li says.


CORRECTION: On March 8, 2017, this story was updated to correct the location of a sulfur atom in the structure of the reduced-holomycin/metal complex.

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Comments
Robert Woodman (March 3, 2017 12:30 PM)
The structure you have drawn for the reduced-homomycin/metal complex is not what is shown in the PNAS paper. The sulfur does not rearrange as you have drawn it.
Stu Borman (March 6, 2017 1:11 PM)
I'm sorry about this structure error, and thanks for finding it. C&E News will be posting correction notices both online and in print.

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