Featured Research

from universities, journals, and other organizations

Anthrax Toxin Inhibitor Identified; Findings Could Lead To More Effective Therapy For Deadly Agent

Date:
December 30, 2003
Source:
Harvard Medical School
Summary:
A research team led by scientists at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS) has identified a group of small molecules that inhibit a deadly toxin associated with inhalational anthrax.

BOSTON -- A research team led by scientists at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS) has identified a group of small molecules that inhibit a deadly toxin associated with inhalational anthrax. Described in the January 2004 issue of Nature Structural & Molecular Biology, these findings could eventually lead to the development of a protease inhibitor drug, which in combination with antibiotics could be used to treat anthrax cases later in the disease, at a point when antibiotics alone are no longer effective.

"Unlike most types of bacteria, Bacillus anthracis has the ability to produce large amounts of a toxin that can kill the patient even after antibiotics have destroyed the bacteria," explains the study's senior author Lewis Cantley, Ph.D., Chief of the Division of Signal Transduction at BIDMC and Professor of Systems Biology at HMS. "This toxin is released within days of the initial infection, and is impervious to antibiotics." Because the initial symptoms of the disease – fever, cough and chest pain – mimic colds and flu, early diagnosis is extremely difficult; as a result, some 90 percent of all cases of inhalational anthrax prove fatal.

"Toxins act in two ways," adds BIDMC scientist and first author Benjamin Turk, Ph.D. "First, they cripple the cells that fight bacterial infection, thereby enabling the spread of bacteria early in the disease. Later in the process," he adds, "they contribute to the death of macrophage cells, leading to the shutdown of the body's immune system." In fact, autopsies of patients who have died from inhalational anthrax reveal that the high doses of antibiotics have killed the bacteria, indicating that the patients have died from the toxins rather than a persistent infection.

Using a "mixture-based peptide library" technique developed by Turk, the researchers analyzed trillions of peptides to determine an optimal peptide substrate for lethal factor, the active agent in the anthrax toxin. Based on the structure of the optimal substrate, small molecule inhibitors were identified. Finally, crystal structures of lethal factor protease bound to its optimal substrate and to small molecule inhibitors revealed new approaches to enable the design of better inhibitors that might prove effective for clinical use.

The mechanism by which anthrax lethal factor kills human cells is not yet clear. The protease activity of this toxin is known to attack a family of protein kinases called map kinase kinases (MEKKs), which mediate many cellular responses, including cytokine release and cell survival. The availability of drug inhibitors may facilitate the understanding of the effect of lethal factor on these pathways. Protease inhibitor drugs have gained popularity in recent years, notably in the treatment of HIV infections. They work by disabling native protease enzymes and like a key fitting perfectly into a lock, "lock up" the enzyme, rendering it ineffectual

"There could be a number of advantages to taking this approach in attacking inhalational anthrax," notes Cantley. "Unlike an anti-serum, which would require that whole populations be vaccinated -- regardless of whether or not an anthrax outbreak developed -- a therapeutic combination of antibiotics and protease inhibitor drugs wouldn't have to be used except in the incidence of actual disease. This approach would not only reduce the risk of side effects, but could also prove cost effective."

Study coauthors include Robert Liddington, Ph.D., Thiang Yian Wong, Ph.D., and Robert Schwarzenbacher, Ph.D., of The Burnham Institute, La Jolla, California; R. John Collier, Ph.D., of the Department of Microbiology and Molecular Genetics, Harvard Medical School; and Emily Jarrell of BIDMC.

Funding for this study came from the National Institutes of Health, the U.S. National Science Foundation and the U.S. Army.


Story Source:

The above story is based on materials provided by Harvard Medical School. Note: Materials may be edited for content and length.


Cite This Page:

Harvard Medical School. "Anthrax Toxin Inhibitor Identified; Findings Could Lead To More Effective Therapy For Deadly Agent." ScienceDaily. ScienceDaily, 30 December 2003. <www.sciencedaily.com/releases/2003/12/031230015204.htm>.
Harvard Medical School. (2003, December 30). Anthrax Toxin Inhibitor Identified; Findings Could Lead To More Effective Therapy For Deadly Agent. ScienceDaily. Retrieved July 22, 2014 from www.sciencedaily.com/releases/2003/12/031230015204.htm
Harvard Medical School. "Anthrax Toxin Inhibitor Identified; Findings Could Lead To More Effective Therapy For Deadly Agent." ScienceDaily. www.sciencedaily.com/releases/2003/12/031230015204.htm (accessed July 22, 2014).

Share This




More Health & Medicine News

Tuesday, July 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
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
Tooth Plaque Provides Insight Into Diets Of Ancient People

Tooth Plaque Provides Insight Into Diets Of Ancient People

Newsy (July 19, 2014) Research on plaque from ancient teeth shows that our prehistoric ancestor's had a detailed understanding of plants long before developing agriculture. Video provided by Newsy
Powered by NewsLook.com
Contaminated Water Kills 3 Babies in South African Town

Contaminated Water Kills 3 Babies in South African Town

AFP (July 18, 2014) Contaminated water in South Africa's northwestern town of Bloemhof kills three babies and hospitalises over 500 people. The incident highlights growing fears over water safety in South Africa. Duration: 02:22 Video provided by AFP
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