May 21, 2013 -- (Bronx, NY) -- In a striking, unexpected discovery, researchers at Albert Einstein College of Medicine of Yeshiva University have determined that vitamin C kills drug-resistant tuberculosis (TB) bacteria in laboratory culture. The finding suggests that vitamin C added to existing TB drugs could shorten TB therapy, and it highlights a new area for drug design. The study was published today in the online journal Nature Communications.
TB is caused by infection with the bacterium M. tuberculosis. In 2011, TB sickened some 8.7 million people and took some 1.4 million lives, according to the World Health Organization. Infections that fail to respond to TB drugs are a growing problem: About 650,000 people worldwide now have multi-drug-resistant TB (MDR-TB), 9 percent of whom have extensively drug-resistant TB (XDR-TB).TB is especially acute in low and middle income countries, which account for more than 95 percent of TB-related deaths, according to the World Health Organization.
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.
"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."
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.
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.
About Albert Einstein College of Medicine of Yeshiva University
Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. During the 2012-2013 academic year, Einstein is home to 742 M.D. students, 245 Ph.D. students, 116 students in the combined M.D./Ph.D. program, and 360 postdoctoral research fellows. The College of Medicine has more than 2,000 full-time faculty members located on the main campus and at its clinical affiliates. In 2012, Einstein received over $160 million in awards from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore Medical Center, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Through its extensive affiliation network involving Montefiore, Jacobi Medical Center -Einstein's founding hospital, and five other hospital systems in the Bronx, Manhattan, Long Island and Brooklyn, Einstein runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States. For more information, please visit http://www.