TB treatment from the toothbrush tree

Tuberculosis is the world’s most deadly infectious disease. Around 1.8 million people die each year and about two billion are infected. But the drugs used to treat the disease are almost 50 years old. They have to be taken in long, demanding treatment schedules that often result in non-compliance and drug resistance.

More Medicines For Tuberculosis (MM4TB) is a research consortium formed by 25 laboratories across Europe to discover new drugs to combat the disease. One potential source of new antibiotics is plants used in traditional medicine.

Twigs from the South African toothbrush tree, Euclea natalensis, are used for tooth cleaning and its roots and bark are used in traditional medicine to treat bronchitis, pleurisy, urinary tract infections and venereal disease. Researchers from the John Innes Centre in Norwich, a partner in MM4TB, recently discovered that extracts from Euclea natalensis are active against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. Furthermore, they found that the extracts appear to inactivate an already established drug target for tuberculosis in a novel way.

The extracts’ active component is diospyrin, a naphthoquinone that inhibits the enzyme DNA gyrase, which relaxes DNA supercoiling so that replication can take place. DNA gyrase is a DNA topoisomerase essential to bacteria and plants but not found in animals or humans. It consists of two subunits, GyrA and GyrB. Diospyrin appears to block DNA replication by binding to the B subunit near, but not overlapping, the ATP-binding site.

This mode of action is different from that of other antibacterials that target the same enzyme. Aminocoumarins work by binding to the ATP site on the GyrB subunit while quinolones and fluoroquinolones such as ciprofloxacin bind to the A subunit and interfere with its strand cutting and resealing function.

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