How popular antifungal natamycin works

June 25, 2012 § Leave a comment

Structure of natamycin.

It’s funny how little we know about the mechanisms of some substances we come across every day. Take natamycin, for example. It’s an antifungal agent produced by a bacterium that has been used for ages by the food industry to stop fungal growth in dairy products and other foods. It’s also used as a topical antifungal agent in eyedrops, skin creams and lozenges. Despite its widespread use, no one really knows how it does its job of stopping fungi and yeast from growing.

Now researchers in The Netherlands, including Eefjan Breukink at Utrecht University, have figured out how natamycin struts its stuff. In a paper due to come out this week in the Proceedings of the National Academy of Sciences, Breukink and colleagues demonstrated that the compound inhibits the transport of amino acids and glucose across the plasma membrane of fungal and yeast cells.

To be effective, natamycin relies on the presence of ergosterol in the plasma membrane of cells, a lipid sterol that is specific to fungi and yeast. Breukink and colleagues suggest that natamycin somehow interferes with interactions between ergosterol and the transport proteins in the plasma membrane, which chokes the transport of goods into the cell.

Natamycin’s inhibition of transport seems to be a blanket inhibition. “Transporters seem to be blocked irrespective of their localization” in lipid rafts or not, says Breukink. He adds the finding seems to indicate that there is “a general role of sterols in the functioning of membrane proteins.”

Figuring out natamycin’s mode of action has implications for antifungal drug development. Breukink says that the work highlights that an antifungal agent doesn’t have to punch a hole in the plasma membrane to kill cells, which is a common mode of action for other antifungals.

Indeed, there is a desperate need to find new agents to fight fungal infections. The researchers point out in their introduction that fungal infection is on the rise worldwide but “the therapeutic arsenal is limited and the use of drugs is restricted as a result of toxicity or unfavorable pharmacokinetic profiles.”

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