Enzyme-targeting uncouplers may lead to novel antibiotics

Enzyme-targeting uncouplers may lead to novel antibiotics
 

Faced with mounting antibiotic resistance, researchers are seeking new types of antibiotics. One approach is focused on compounds called uncouplers, which block ATP biosynthesis and can inhibit additional metabolic pathways in bacteria.

Because this dual target approach might be less toxic to host cells than uncouplers alone and less susceptible to acquired resistance, researchers tested a series of compounds—most of which have proven antiinfective activity—and found that a widely prescribed infertility drug exhibits potent uncoupler activity.

The drug, called clomiphene, inhibits a bacterial cell wall biosynthesis enzyme and kills Staphylococcus aureus, a bacterium responsible for drug-resistant infections.

Using computer simulations, the authors also determined that the brain cancer drug candidate vacquinol acts as an uncoupler in Mycobacterium, the bacterium that causes tuberculosis in humans, and inhibits a bacterial enzyme that blocks host cell immune responses.

The findings, according to the authors, suggest that screening for compounds that can act as both uncouplers and inhibitors of key bacterial enzymes may yield promising new antibiotic candidates.

http://www.pnas.org/content/early/2015/12/03/1521988112

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