Potential Tuberculosis Drug Prevents DNA Supercoiling

A recent paper described the molecular mechanism that allows the drug diospyrin to block the growth of the tuberculosis bacterium Mycoplasma tuberculosis.

Diospyrin is a dimeric naphthoquinone isolated from the root of Diospyros piscatoria (Gurke), a common ingredient in several folk medicines, which has been shown to have a broad spectrum of antibacterial activity. Previous studies have shown that diospyrin binds to a novel site on the enzyme DNA gyrase and inactivates it. DNA gyrase is essential for bacteria and plants but is not present in animals or humans.

DNA gyrase is a type II topoisomerase that introduces negative supercoils into DNA by looping the template so as to form a crossing, then cutting one of the double helices and passing the other through it before releasing the break, changing the linking number by two in each enzymatic step. This process occurs particularly in bacteria, where single circular DNA is cut by DNA gyrase, and the two ends are then twisted around each other to form supercoils.

Supercoiling is the coiling of an already coiled structure (such as DNA). DNA is coiled around itself for several reasons: the three-dimensional structure of DNA affects its function; the coiling can have positive or negative effects on gene expression; and the unraveling of portions of a circular bacterial chromosome during transcription could induce coiling that could prevent the strands for reattaching to one another. Supercoiling in the opposite direction will cancel out coiling problems during transcription. Coiling DNA in multiple directions reduces the space occupied by DNA and makes the structure more stable during replication and transcription.

In a paper published in the December 28, 2012, online edition of the Journal of Biological Chemistry investigators at the John Innes Center (Norfolk, United Kingdom) reported that diospyrin and related naphthoquinone compounds bound to the N-terminal domain of DNA gyrase, which contains the ATPase active site, but were not competitive inhibitors of the ATPase reaction. Therefore, naphthoquinones bound to the enzyme at a previously undefined site close to the ATPase site.

"The way that diospyrin works helps to explain why it is effective against drug-sensitive and drug-resistant strains of tuberculosis," said senior author Dr. Tony Maxwell, professor of biological chemistry at the John Innes Center.

"Extracts from plants used in traditional medicine provide a source for novel compounds that may have antibacterial properties, which may then be developed as antibiotics," said Dr. Maxwell. "This highlights the value of ethnobotany and the value of maintaining biodiversity to help us address global problems."

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