Vitamin C Kills Drug-Resistant Mycobacterium tuberculosis, Study Shows

Scientists at the Albert Einstein College of Medicine in New York have unexpectedly discovered that vitamin C can kill drug-resistant tuberculosis bacteria.

This scanning electron micrograph shows some of the ultrastructural details seen in the cell wall configuration of a number of Mycobacterium tuberculosis bacteria (Janice Haney Carr)

This scanning electron micrograph shows some of the ultrastructural details seen in the cell wall configuration of a number of Mycobacterium tuberculosis bacteria (Janice Haney Carr)

The findings, published in the journal Nature Communications, suggest that vitamin C added to existing anti-tuberculosis drugs could shorten therapy, and highlight a new area for drug design.

Tuberculosis is caused by infection with the bacterium Mycobacterium tuberculosis. The disease is especially acute in low and middle income countries, which account for more than 95 percent of tuberculosis-related deaths, according to the World Health Organization.

Infections that fail to respond to anti-tuberculosis drugs are a growing problem: about 650,000 people worldwide now have multi-drug-resistant tuberculosis, 9 percent of whom have extensively drug-resistant tuberculosis.

The discovery arose during research into how tuberculosis bacteria become resistant to isoniazid, a potent first-line anti-tuberculosis drug.

The scientists observed that isoniazid-resistant tuberculosis bacteria were deficient in a molecule called mycothiol.

“We hypothesized that tuberculosis bacteria that can’t make mycothiol might contain more cysteine, an amino acid,” explained senior author Prof William Jacobs.

“So, we predicted that if we added isoniazid and cysteine to isoniazid-sensitive Mycobacterium tuberculosis in culture, the bacteria would develop resistance. Instead, we ended up killing off the culture – something totally unexpected.”

The team suspected that cysteine was helping to kill tuberculosis bacteria by acting as a reducing agent that triggers the production of reactive oxygen species, which can damage DNA.

Action of vitamin C against Mycobacterium tuberculosis: vitamin C enters Mycobacterium tuberculosis cells and reduces ferric ions to generate ferrous ions that, in presence of oxygen, will produce superoxide, hydrogen peroxide and hydroxyl radicals; the production of these reactive oxygen species leads to the DNA damage, alteration of lipids and redox balance (Catherine Vilchèze et al)

Action of vitamin C against Mycobacterium tuberculosis: vitamin C enters Mycobacterium tuberculosis cells and reduces ferric ions to generate ferrous ions that, in presence of oxygen, will produce superoxide, hydrogen peroxide and hydroxyl radicals; the production of these reactive oxygen species leads to the DNA damage, alteration of lipids and redox balance (Catherine Vilchèze et al)

“To test this hypothesis, we repeated the experiment using isoniazid and a different reducing agent – vitamin C. The combination of isoniazid and vitamin C sterilized the Mycobacterium tuberculosis culture. We were then amazed to discover that vitamin C by itself not only sterilized the drug-susceptible tuberculosis, but also sterilized multi-drug-resistant tuberculosis and extensively drug-resistant strains,” Prof Jacobs said.

To justify testing vitamin C in a clinical trial, the team needed to find the molecular mechanism by which vitamin C exerted its lethal effect.

More research produced the answer – vitamin C induced what is known as a Fenton reaction, causing iron to react with other molecules to create reactive oxygen species that kill the tuberculosis bacteria.

“We don’t know whether vitamin C will work in humans, but we now have a rational basis for doing a clinical trial. It also helps that we know vitamin C is inexpensive, widely available and very safe to use. At the very least, this work shows us a new mechanism that we can exploit to attack tuberculosis,” Prof Jacobs concluded.

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Bibliographic information: Catherine Vilchèze et al. 2013. Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nature Communications 4, article number: 1881; doi: 10.1038/ncomms2898