Navigation Links
Potential new drug target to fight tuberculosis identified
Date:7/30/2008

NEW YORK (July 29, 2008) -- With antibiotic resistance on the rise, tuberculosis is emerging as a bigger global health threat than ever before.

But now, innovative research at Weill Cornell Medical College suggests that Mycobacterium tuberculosis has an as yet unsuspected weakness -- one that could be a prime target for drug development.

"Using novel techniques, we have identified a key membrane protein that's essential to the defense that M. tuberculosis mounts against the acidic environment of immune cells called macrophages. Without this protein, called Rv3671c, the bacterium becomes vulnerable to acidification and is killed," explains lead author Omar H. Vandal, a postdoctoral fellow in the lab of study co-senior author Dr. Sabine Ehrt, associate professor of microbiology and immunology at Weill Cornell Medical College.

"M. tuberculosis does not depend on Rv3671c under standard growth conditions in the test tube, so it has been overlooked as a candidate drug target," says Dr. Carl F. Nathan, also a senior author of the study and the R.A. Pritchett Professor of Microbiology. He is also chairman of the Department of Microbiology and Immunology at Weill Cornell.

Drs. Ehrt and Nathan co-supervised Dr. Vandal in this work while Dr. Vandal was a student at the Weill Cornell Graduate School of Medical Sciences. "However, when M. tuberculosis infects the host, then the Rv3671c protein becomes essential," added Dr. Ehrt. "This is an example of a new class of potential targets for anti-infective agents," continues Dr. Nathan, "those that the pathogen only needs in order to survive in the host environment."

The research was just published in Nature Medicine.

In numerous papers published in leading journals, Dr. Nathan has long pushed for an innovative approach to the development of anti-infective agents that goes beyond the traditional antibiotic paradigm. "That's exactly what we sought to do in this research," he says.

One of the study's innovations involved the examination of M. tuberculosis as it interacted with bone marrowderived macrophages during the infective process.

"That's a huge change from standard anti-infective research, which typically deals with the pathogen simply replicating in culture," explains Dr. Vandal. "In our experiments, we wanted to see if biochemical actors would emerge in the infective process that might be inoperative in the usual in vitro setting."

The team specifically focused on changes in the pH (acidity) of the phagosome -- a structure that macrophages use to consume and destroy pathogens, including bacteria.

"As part of this process, the phagosome becomes acidic, which is thought to contribute to its ability to break down and destroy the pathogen," Dr. Ehrt explains. "However, M. tuberculosis appears to survive the acidification process, keeping its own internal pH stable."

How does the bacteria do this, despite being surrounded by the more highly acidic phagosome? To find out, the team used a kind of genetic tweaking that effectively disabled M.tuberculosis' ability to produce a key protein lying at its membrane -- a protease (enzyme) called Rv3671c.

They then watched how the organism fared without it.

"What we observed was pretty amazing -- without functioning Rv3671c, the mutant bacterium was easily destroyed in a low-pH environment, both in culture and inside the more acidic environment of the macrophage," says Dr. Vandal. "This revealed a new point of vulnerability for the bacterium."

The experiment also broke new ground because the researchers were able to accurately gauge the bacterium's internal pH with the organism lying inside a host cell.

"The ability to make those kinds of measurements will expand research into this type of host-pathogen interaction," Dr. Nathan believes.

The next step is to find out why Rv3671c is so crucial to M. tuberculosis' defense.

"Right now, we have very little idea of the mechanism at work here. Perhaps as an enzyme Rv3671c cleaves a transcription regulator that then turns on some kind of defensive program within the bacterium. Only further study will reveal those secrets," says Dr. Ehrt.

"What is clear is that by targeting an element involved directly in the infective process, we may develop a line of drugs that work in collaboration with, rather than in difference to, the host environment, including host immune responses," Dr. Nathan says. "Hopefully, this kind of approach can help solve the ongoing problem of bacterial drug resistance."

The new study is also another example of an interdisciplinary approach -- this time among biochemists, microbiologists, immunologists and cell biologists.

"In the ideal collaboration, each participant brings key insights from their particular discipline to the table," Dr. Nathan says. "The results are discoveries like these."


'/>"/>

Contact: Andrew Klein
ank2017@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College
Source:Eurekalert

Related biology news :

1. Researchers tap into a new and potentially better source of platelets for transfusion
2. TG2 identified as potential therapeutic target in chemo-resistant ovarian cancer
3. UC San Diego researchers identify potential new drug candidates to combat bird flu
4. New oral angiogenesis inhibitor offers potential nontoxic therapy for a wide range of cancers
5. The good and the bad of a potential Alzheimers target
6. Stanford study: Bioenergy potential of reviving abandoned agricultural land
7. Indiana U scientists uncover potential key to better drugs to fight toxoplasmosis parasite
8. Scientists find potential protein biomarkers for growth hormone
9. New technology enhances therapeutic potential of cord blood stem cells
10. Potential therapy discovered for hypophosphatasia, a congenital form of rickets
11. Compound has potential for new class of AIDS drugs
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:12/20/2016)... 20, 2016   Valencell , the leading ... STMicroelectronics (NYSE: STM), a global semiconductor leader ... announced today the launch of a new, highly ... that includes ST,s compact SensorTile turnkey ... biometric sensor system. Together, SensorTile and Benchmark deliver ...
(Date:12/16/2016)... global wearable medical device market, in terms of value, is projected ... in 2016, at a CAGR of 18.0% during the forecast period. ... Growth in ... launch of a growing number of smartphone-based healthcare apps compatible with ... increasing focus on physical fitness. Furthermore, growing trend ...
(Date:12/15/2016)... LONDON , Dec. 15, 2016 /PRNewswire/ ... the driving experience, health wellness and wellbeing ... As one in three new passenger vehicles ... voice recognition, gesture recognition, heart beat monitoring, ... eyelid monitoring, facial monitoring, and pulse detection. ...
Breaking Biology News(10 mins):
(Date:1/20/2017)... , January 20, 2017 ... cancer is one of leading causes of death worldwide. ... Although the number of cancer related deaths increased gradually ... Rising in incidence rate of various cancers continues to ... a research report by Global Market Insights, Inc. cancer ...
(Date:1/19/2017)... , Jan. 19, 2017 /PRNewswire -- WuXi AppTec, ... open-access capability and technology platform, today announced that ... biology focused preclinical drug discovery contract research organization ... become a wholly-owned subsidiary of WuXi, and will ... and providing greater services. The acquisition will further ...
(Date:1/19/2017)... Jan. 19, 2017  ArmaGen, Inc., today announced ... Ph.D., as chief executive officer, as well as ... brings to ArmaGen more than 17 years of ... development of biotherapeutics and pharmaceuticals. ... diverse experience and skillset necessary to lead ArmaGen ...
(Date:1/19/2017)... ... January 19, 2017 , ... ... the full spectrum of drug and device development, and Prism Clinical Research ... and clinicians, today announced Verified Clinical Trials (VCT) has been selected ...
Breaking Biology Technology: