Featured Research

from universities, journals, and other organizations

New findings on drug tolerance in TB suggest ideas for shorter cures

Date:
March 4, 2011
Source:
University of Washington
Summary:
A study of host-pathogen responses in tuberculosis elucidates molecular mechanisms of antibiotic tolerance in tuberculosis and further suggests a strategy for shortening curative therapy (currently six months) using a class of drugs -- efflux pump inhibitors -- that are already approved for treating high blood pressure and angina, and available for use in people.

New findings on how tuberculosis (TB) bacteria develop multi-drug tolerance point to ways TB infections might be cured more quickly. The results identify both a mechanism and a potential therapy for drug tolerance that is induced in the TB bacteria by the host cells they infect.

The study will be published April 1 in the journal Cell.

Currently, TB treatment requires a complex, long-term curative regimen of at least six months, explained the senior author of the study, Dr. Lalita Ramakrishnan, University of Washington (UW) professor of medicine, microbiology and immunology. Her lab conducted the study in collaboration with Dr. Paul Edelstein, of the Department of Pathology and Laboratory Medicine at the University of Pennsylvania.

Many months of TB treatment are needed because the bacteria become tolerant to TB drugs. In the first couple days of treatment the bacteria die rapidly, but the death rate then slows to a crawl as the bacteria become resistant to killing. This tolerance to antibiotics occurs despite the absence of genetic mutations for drug resistance.

The authors noted that adhering to six months of drug treatment is difficult, particularly in areas of the world where TB is prevalent.

"Breaks in treatment can lead to relapses that perpetuate the TB epidemic and also fuel the development of genetic resistance to treatment," Edelstein said.

An urgent goal of scientists is to overcome drug tolerance, yet most of the drugs in development will not shorten the lengthy treatment. This failure results from a poor understanding of the mechanism of TB tolerance.

"Drug tolerance," Ramakrishnan said, "has been largely attributed to TB bacteria that are dormant in the body and not reproducing. These postulated dormant bacteria are thought to be unaffected by the administered antibiotics that are most effective against rapidly growing organisms"

In this latest study, the researchers draw another picture of what might be happening in TB. They described the existence of multi-drug tolerant organisms that form within days of infection in zebrafish, an animal model for studying TB. However, they were surprised to see this bacterial population actively growing and reproducing inside of host macrophages -- "big eater" white blood cells that engulf germs and debris in the body. In fact, the drug-tolerant bacteria not only thrive within these disease-fighting clean-up cells, but also co-opt them to carry the transiently drug resistant TB infection to other parts of the body. There they help promote its continuation inside of granulomas -- the nodules in the lung characteristic of TB.

To understand how growing bacteria might be tolerant to drugs, the authors turned to studying the human TB bacillus in human macrophages. They found that upon infecting macrophages, the bacteria deploy a structure called an efflux pump. The authors found that these pumps are essential for the TB bacteria to grow within macrophages and are turned on possibly to get rid of host antimicrobial substances targeted to penetrate the bacteria and destroy them.

Paradoxically it is the infected macrophage itself that stimulates the efflux pumps in the bacteria. The TB cell efflux pumps can also flush away medications, a mechanism, the researchers say, which may be contributing to multi-drug tolerance.

"Thus the TB drugs get caught in the crossfire in this pitched battle between bacterium and host," Ramakrishnan said.

Certain inexpensive medications are already available that can inhibit these bacterial pumps and thereby reduce multi-drug tolerance, the researchers noted. One of these is the calcium channel blocker verapamil, which is used to treat high blood pressure, angina, and some heart rhythm problems.

The researchers suggest that adding this currently approved drug to TB therapy, or working to develop drugs that more specifically block the bacterial efflux pumps in TB organisms, might reduce multi-drug tolerance. If so, efflux pump inhibitors might be able to shorten the duration of curative treatment for TB.

This study was supported by a Bill & Melinda Gates Foundation TB drug accelerator grant, a UW Royalty Research Fund Grant, a Burroughs Wellcome Foundation Pathogenesis of Infectious Diseases Award, grants from the National Institutes of Health, a Levinson Emerging Scholars Program Grant, a Mary Gates Endowment Grant, a NASA Space Grant, and a Pfizer Fellowship in Infectious Diseases. Ramakrishnan is a recipient of the NIH Director's Pioneer Award.

In addition to Ramakrishnan and Edelstein, the research team included Kristin Adams and Kevin Takaki, both lead authors of this paper, together with Lynn Connolly, Heather Wiedenhoft, Kathryn Winglee, Olivier Humbert, and Christine Cosma. Connolly is now on the faculty of the Department of Medicine at the University of California, San Francisco; and Winglee, who was a UW undergraduate when she performed the work, is a doctoral student at Johns Hopkins University.


Story Source:

The above story is based on materials provided by University of Washington. Note: Materials may be edited for content and length.


Journal Reference:

  1. Kristin N. Adams, Kevin Takaki, Lynn E. Connolly, Heather Wiedenhoft, Kathryn Winglee, Olivier Humbert, Paul H. Edelstein, Christine L. Cosma, Lalita Ramakrishnan. Drug Tolerance in Replicating Mycobacteria Mediated by a Macrophage-Induced Efflux Mechanism. Cell, March 3, 2011 DOI: 10.1016/j.cell.2011.02.022

Cite This Page:

University of Washington. "New findings on drug tolerance in TB suggest ideas for shorter cures." ScienceDaily. ScienceDaily, 4 March 2011. <www.sciencedaily.com/releases/2011/03/110303132345.htm>.
University of Washington. (2011, March 4). New findings on drug tolerance in TB suggest ideas for shorter cures. ScienceDaily. Retrieved September 23, 2014 from www.sciencedaily.com/releases/2011/03/110303132345.htm
University of Washington. "New findings on drug tolerance in TB suggest ideas for shorter cures." ScienceDaily. www.sciencedaily.com/releases/2011/03/110303132345.htm (accessed September 23, 2014).

Share This



More Health & Medicine News

Tuesday, September 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Liberia Pleads for Help to Fight Ebola

Liberia Pleads for Help to Fight Ebola

AP (Sep. 22, 2014) Liberia's finance minister is urging the international community to quickly follow through on pledges of cash to battle Ebola. Bodies are piling up in the capital Monrovia as the nation awaits more help. (Sept. 22) Video provided by AP
Powered by NewsLook.com
Ebola Doctor Says Border Controls Critical

Ebola Doctor Says Border Controls Critical

AP (Sep. 22, 2014) A Florida doctor who helped fight the expanding Ebola outbreak in West Africa says the disease can be stopped, but only if nations quickly step up their response and make border control a priority. (Sept. 22) Video provided by AP
Powered by NewsLook.com
Global Ebola Aid Increasing But Critics Say It's Late

Global Ebola Aid Increasing But Critics Say It's Late

Newsy (Sep. 21, 2014) More than 100 tons of medical supplies were sent to West Africa on Saturday, but aid workers say the global response is still sluggish. Video provided by Newsy
Powered by NewsLook.com
Sierra Leone in Lockdown to Control Ebola

Sierra Leone in Lockdown to Control Ebola

AP (Sep. 21, 2014) Sierra Leone residents remained in lockdown on Saturday as part of a massive effort to confine millions of people to their homes in a bid to stem the biggest Ebola outbreak in history. (Sept. 20) Video provided by AP
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:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

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