Featured Research

from universities, journals, and other organizations

Experimental TB Drug Explodes Bacteria From The Inside Out

Date:
November 28, 2008
Source:
NIH/National Institute of Allergy and Infectious Diseases
Summary:
Biochemists have discovered how an experimental drug unleashes its destructive force inside the bacteria that cause tuberculosis. The finding could help scientists develop ways to treat dormant TB infections, and suggests a strategy for drug development against other bacteria as well.

An international team of biochemists has discovered how an experimental drug unleashes its destructive force inside the bacteria that cause tuberculosis (TB). The finding could help scientists develop ways to treat dormant TB infections, and suggests a strategy for drug development against other bacteria as well.

A report describing the research, led by Clifton E. Barry, III, Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is published in the Nov. 28 issue of Science. Dr. Barry's collaborators included scientists from NIAID and from the Novartis Institute for Tropical Diseases in Singapore.

One-third of the world's population is infected with Mycobacterium tuberculosis (M. tb), the bacteria that cause TB. "Currently, there are no drugs available that specifically target latent tuberculosis infections in which bacteria are present but are not actively dividing," notes NIAID Director Anthony S. Fauci, M.D. "Dr. Barry and his colleagues have now given us a detailed picture of how the candidate TB drug PA-824 is metabolized inside Mycobacterium tuberculosis. Their discovery is a promising step towards developing effective drugs against latent TB as well as other bacteria."

Previously, Dr. Barry and his collaborators found that M. tb mutants lacking a specific bacterial enzyme were resistant to PA-824, but at that time, they did not know the function of the enzyme.

"It took several years, but at last we were able to recreate in the test tube what happens inside mycobacterial cells when the bacterial enzyme, which we named Ddn, and a second bacterial component called a cofactor, interact with PA-824," says Dr. Barry. The key event in PA-824 metabolism, they found, is the production of nitric oxide (NO) gas. "This highly reactive molecule," he adds, "is akin to a bomb blast that kills the bacteria from within."

NO gas is produced naturally by certain immune system cells after they engulf M. tb or other bacteria. This is one way that people with healthy immune systems can contain M. tb infection. However, this natural immune response is not always enough to completely rid the body of TB bacteria. In essence, PA-824 performs similarly to the NO-producing immune cells--but the drug's effect is more specific and triggered only after it enters the bacteria.

The non-dividing M. tb bacteria characteristic of latent TB infections are walled off by immune cells that aggregate around the bacteria to form a body called a granuloma. Oxygen levels are low inside granulomas. In their latest research, the scientists observed that NO-generation during PA-824 metabolism is greatest when oxygen levels are low. This observation suggests how PA-824 may work against non-dividing M. tb.

PA-824 was originally designed to work best under aerobic, or oxygenated, conditions. With this new understanding of how the bacterial enzyme and cofactor act on PA-824 under low-oxygen conditions, Dr. Barry says, scientists can design drugs with a chemical structure similar to PA-824 but optimize them from the start to behave best under low-oxygen conditions. This work is already proceeding in the laboratory at NIAID and in partnership with collaborators from the Novartis Institute for Tropical Diseases in Singapore as well as with scientists from the Genomics Institute of the Novartis Research Foundation in San Diego.

Because humans have neither the bacterial cofactor nor any enzymes equivalent to Ddn, PA-824 has no effect on human cells. Conversely, many bacteria have enzymes in the same family as Ddn. Thus, says Dr. Barry, it is possible to envision new kinds of NO-generating drugs designed to interact with enzymes associated with other disease-causing bacteria as well.

In addition to NIAID funding, this research received grant support through the Grand Challenges in Global Health Program, which is jointly funded by the Bill & Melinda Gates Foundation and the Wellcome Trust.

Background Information

In 2000, Dr. Barry and colleagues at NIAID collaborated with the Seattle-based firm PathoGenesis to publish the first description of PA-824. PA-824 entered human clinical trials in 2005. The M. tb enzyme now named Ddn was first described by Dr. Barry and his colleagues in 2005.


Story Source:

The above story is based on materials provided by NIH/National Institute of Allergy and Infectious Diseases. Note: Materials may be edited for content and length.


Journal Reference:

  1. R Singh et al. Bicyclic nitroimidazoles are intracellular NO donors and kill non-replicating Mycobacterium tuberculosis. Science, 2008 DOI: 10.1126/science.1164571

Cite This Page:

NIH/National Institute of Allergy and Infectious Diseases. "Experimental TB Drug Explodes Bacteria From The Inside Out." ScienceDaily. ScienceDaily, 28 November 2008. <www.sciencedaily.com/releases/2008/11/081127145137.htm>.
NIH/National Institute of Allergy and Infectious Diseases. (2008, November 28). Experimental TB Drug Explodes Bacteria From The Inside Out. ScienceDaily. Retrieved July 23, 2014 from www.sciencedaily.com/releases/2008/11/081127145137.htm
NIH/National Institute of Allergy and Infectious Diseases. "Experimental TB Drug Explodes Bacteria From The Inside Out." ScienceDaily. www.sciencedaily.com/releases/2008/11/081127145137.htm (accessed July 23, 2014).

Share This




More Plants & Animals News

Wednesday, July 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Michigan Plant's Goal: Flower and Die

Michigan Plant's Goal: Flower and Die

AP (July 22, 2014) An 80-year-old agave plant, which is blooming for the first and only time at a University of Michigan conservatory, will die when it's done (July 22) Video provided by AP
Powered by NewsLook.com
San Diego Zoo Welcomes New, Rare Rhino Calf

San Diego Zoo Welcomes New, Rare Rhino Calf

Reuters - US Online Video (July 21, 2014) An endangered black rhino baby is the newest resident at the San Diego Zoo. Sasha Salama reports. Video provided by Reuters
Powered by NewsLook.com
Shark Sightings a Big Catch for Cape Tourism

Shark Sightings a Big Catch for Cape Tourism

AP (July 21, 2014) A rise in shark sightings along the shores of Chatham, Massachusetts is driving a surge of eager vacationers to the beach town looking to catch a glimpse of a great white. (July 21) Video provided by AP
Powered by NewsLook.com
$23.6 Billion Awarded To Widow In Smoking Lawsuit

$23.6 Billion Awarded To Widow In Smoking Lawsuit

Newsy (July 20, 2014) Cynthia Robinson claims R.J. Reynolds Tobacco Company hid the health and addiction risks of its products, leading to the death of her husband in 1996. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins