The Einstein discovery arose during research into how TB bacteria become resistant to isoniazid, a potent first-line TB drug. The lead investigator and senior author of the study was William Jacobs, Jr., Ph.D., professor of microbiology & immunology and of genetics at Einstein. Dr. Jacobs is a Howard Hughes Medical Institute investigator and a recently elected member of the National Academy of Sciences.
Dr. Jacobs and his colleagues observed that isoniazid-resistant TB bacteria were deficient in a molecule called mycothiol. “We hypothesized that TB bacteria that can’t make mycothiol might contain more cysteine, an amino acid,” said Dr. Jacobs. “So, we predicted that if we added isoniazid and cysteine to isoniazid-sensitive M. tuberculosis in culture, the bacteria would develop resistance. Instead, we ended up killing off the culture— something totally unexpected.”
The Einstein team suspected that cysteine was helping to kill TB bacteria by acting as a “reducing agent” that triggers the production of reactive oxygen species (sometimes called free radicals), which can damage DNA.
“We predicted that if we added isoniazid and cysteine to isoniazid-sensitive M. tuberculosis in culture, the bacteria would develop resistance. Instead, we ended up killing off the culture— something totally unexpected.”
– William Jacobs, Jr., Ph.D.
“To test this hypothesis, we repeated the experiment using isoniazid and a different reducing agent— vitamin C,” said Dr. Jacobs. “The combination of isoniazid and vitamin C sterilized the M. tuberculosis culture. We were then amazed to discover that vitamin C by itself not only sterilized the drug-susceptible TB, but also sterilized MDR-TB and XDR-TB strains.”
To justify testing vitamin C in a clinical trial, Dr. Jacobs 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 TB bacteria.
“We don’t know whether vitamin C will work in humans, but we now have a rational basis for doing a clinical trial,” said Dr. Jacobs. “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 TB.”
About Drug-Resistant TB
Multi-drug-resistant TB (MDR-TB): TB that does not respond to isoniazid and rifampicin, the two most potent anti-TB drugs.
Extensively drug-resistant TB (XDR-TB):
TB that is resistant to rifampicin and isoniazid, as well as to any member of the quinolone family of antibiotics and at least one of four second-line injectable anti-TB drugs.
The paper is titled, “Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction.” The other contributors are Catherine Vilcheze, Ph.D., Travis Hartman and Brian Weinrick, Ph.D., all at Einstein.
The study was supported by a grant (AI26170) from National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.
The authors declare no conflict of interest.
Albert Einstein College of Medicine