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

New findings on how tuberculosis (TB) bacteria develop multi-drug tolerance point to ways TB infections might be cured more quickly.

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

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.


Contact: Leila Gray
University of Washington

Related medicine news :

1. Latest findings of Dartmouth HIV/AIDS study could turn treatment on its head
2. Research provides new findings on drug delivery with nanoparticles
3. SMFM highlights significance of spina bifida research findings
4. Most Guidelines for Infectious Diseases Dont Come From Clinical Trial Findings
5. International research team reports major findings in prevention and treatment of blood clots
6. VCU findings may help explain some major clinical symptoms of preeclampsia
7. Addiction research: Key findings every month
8. Encouraging findings suggest new avenues for treating liver disease in overweight Americans
9. Latest Findings Back Mammograms for Women in Their 40s
10. National committee releases findings on transforming and improving the nursing profession
11. Study findings show value of dietary supplement SAMe in treatment of adults with major depressive disorders
Post Your Comments:
Related Image:
New findings on drug tolerance in TB suggest ideas for shorter cures
(Date:11/26/2015)... ... November 26, 2015 , ... WorldCare International, Inc., ... the 61st annual Employee Benefits Conference. The Employee Benefits Conference was hosted by ... through Wednesday, November 11th, 2015. The conference was held at the Hawaii Convention ...
(Date:11/26/2015)... ... November 26, 2015 , ... Indosoft Inc., developer and distributor of ... server to improve system efficiency and reliability. , The new Q-Suite 6 platform is ... the system avoids locking itself into a specific piece of software for many key ...
(Date:11/25/2015)... ... November 25, 2015 , ... ... preparing the perfect dish and pleasing the palates of attendees is of the ... a dish to a seasonal get-together, give these recipes a try this holiday ...
(Date:11/25/2015)... , ... November 25, 2015 , ... ... offering factory direct sauna parts and accessories. , Sauna accessories help improve the ... bather’s style and personality. From basic styles for the purist looking for simplicity ...
(Date:11/25/2015)... ... ... On November 10, 2015, Bohrer Brady, LLC filed a class and collective ... home health care worker who provided companionship services for the elderly, ill or disabled ... Humana, Inc., Humana at Home, Inc., and SeniorBridge Family Companies (CT), Inc. since January ...
Breaking Medicine News(10 mins):
(Date:11/25/2015)... 2015  Amgen (NASDAQ: AMGN ) today announced ... the United States (U.S.) Food ... candidate to Humira ® (adalimumab). Amgen believes this ... the FDA and represents Amgen,s first BLA submission using ... , M.D., executive vice president of Research and Development ...
(Date:11/25/2015)... -- On Tuesday, November 24, 2015, the jury ... Medical Technology, Inc. for product liability and misrepresentation ... device, awarded $11 million in favor of Plaintiff ... three days of deliberations, the jury found that ... and unreasonably dangerous, and that Wright Medical made ...
(Date:11/25/2015)... Nov. 25, 2015 Allergan plc (NYSE: AGN ... the New York State Attorney General,s ... Sherman Act, and other statutes with the Attorney General over ... to cease marketing and selling the now generic version of ... admits no liability, has released its counterclaims against ...
Breaking Medicine Technology: