Navigation Links
New drug targets may fight tuberculosis and other bacterial infections in novel way

NEW YORK (Dec. 27, 2007) -- Over the course of the 20th Century, doctors waged war against infectious bacterial illness with the best new weapon they had: antibiotics.

But the emergence of dangerous, multi-drug resistant strains of tuberculosis and other killer infections means that in the 21st century antibiotics are losing ground against bacterial disease.

Now, researchers from Weill Cornell Medical College in New York City say exciting new molecular targets -- so-called "virulence factors" that bacteria use to thrive once they are in the host -- present an alternative, potent means of stopping TB, leprosy and other bacterial illness.

"We have developed the first inhibitor of a key small molecule from Mycobacterium tuberculosis and Mycobacterium leprae (which causes leprosy) utilized to subvert human host's defenses and damage and invade human host's cells during infection," explains study senior author Dr. Luis Quadri, Associate Professor of Microbiology and Immunology at Weill Cornell.

"With this work, we now have proof of principle for the inhibition of this virulence factor in bacteria cultured in the lab. Our next step is to explore whether this inhibitor can stop these pathogens from multiplying in a mouse host, curtailing infection," Dr. Quadri says.

The findings -- published online today in Chemistry and Biology and appearing in the journal's Jan. 26 print edition -- highlight what Dr. Quadri has called a "paradigm shift" in infectious disease research.

"We are moving beyond antimicrobials such as antibiotics, which kill the bacterium directly, to anti-infectives, that may have no effect against the pathogen in the test tube but which do compromise its ability to infect and spread in the host," he explains. "We believe that the expansion of the drug armamentarium to include such anti-infective drugs could help the fight against multi-drug resistant infection that has become such a challenge today."

According to World Health Organization data, TB remains one of the world's top-ten leading causes of death, killing nearly two million people each year. Multi-drug resistant strains of M. tuberculosis -- as well as even more dangerous, extensive-drug-resistant (XDR) strains of the bug -- are emerging each year.

"Obviously, we are going to require more than the traditional antimicrobial approach to turn this situation around," Dr. Quadri says.

In this study, Dr. Quadri, along with co-lead researchers Drs. Julian Ferraras and Karen Stirrett, focused on particular small-molecule virulence factors called phenolic glycolipids (PGLs).

Various strains of M. tuberculosis use PGLs to weaken our body defenses whereas M. leprae uses PGLs to damage and invade our nerve cells during infection.

"Therefore, we hypothesize that drugs blocking PGL synthesis would reduce the adaptive fitness of PGL-producing M. tuberculosis strains in the human host by eliminating PGL-dependent immunomodulatory effects. These drugs may also diminish the ability of M. leprae to invade nerve cells and produce nerve function impairment," Dr. Quadri explains.

In complex work in the laboratory, the researchers investigated and then elucidated a crucial, early step in PGL biosynthesis. They also pinpointed a key enzyme, called FadD22, that is essential to that stage of the process.

"Based on that, we collaborated with Dr. Derek Tan's lab at Memorial Sloan-Kettering Cancer Center to synthesize a molecule that targets FadD22 and successfully inhibits that early step in PGL production," Dr. Quadri said.

Follow-up work using both enzyme assays and M. tuberculosis assays confirmed that the new inhibitor does block the production of PGLs. Although it was technically not possible to test the inhibitor in M. leprae, that pathogen is very closely related to M. tuberculosis, so the researchers believe their agent would inhibit production of PGLs there, as well.

Work is already underway to come up with other, even more potent PGL biosynthesis inhibitors, Dr. Quadri says, with an eye to testing the best candidates in an animal model.

"We are not saying that anti-infectives will ever replace antibiotics, but with pathogens as deadly as M. tuberculosis or as debilitating as M. leprae, you'd ideally like to have as many pharmaceutical weapons in your armamentarium as you can, to use either alone or in combination," Dr. Quadri says.

The new discoveries are highly encouraging, he adds.

"I believe that drugs targeting virulence factors are just one component of the paradigm shift in the antimicrobial drug discovery for the 21st century -- one that will offer patients more options in the fight against truly global killers," he says.


Contact: Andrew Klein
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College

Related biology news :

1. Nicotinic receptors may be important targets for treatment of multiple addictions
2. Central targets may hinder wider waste management objectives
3. UIC researchers find promising new targets for antibiotics
4. New X-ray technique targets terrorists and tumors
5. Clemson chemists discover new way antioxidants fight debilitating diseases
6. Social habits of cells may hold key to fighting diseases
7. Advance in effort to fight malaria by tricking the mosquitos sense of smell
8. Yale scientists use nanotechnology to fight E. coli
9. Researchers develop liquid crystal pharmaceuticals to fight cancer and other diseases
10. Japanese beetle may help fight hemlock-killing insect
11. When it comes fighting to C. difficile, the Palme dOr goes to soap and warm water
Post Your Comments:
(Date:6/1/2016)... June 1, 2016 Favorable Government ... Administration and Criminal Identification to Boost Global Biometrics System ... released TechSci Research report, " Global Biometrics Market ... Forecast and Opportunities, 2011 - 2021", the global biometrics ... 2021, on account of growing security concerns across various ...
(Date:5/16/2016)... NEW YORK , May 16, 2016   ... authentication solutions, today announced the opening of an IoT ... to strengthen and expand the development of embedded ... provides an unprecedented level of convenience and security with ... to authenticate one,s identity aside from DNA. EyeLock,s platform ...
(Date:5/3/2016)... 3, 2016  Neurotechnology, a provider of high-precision ... Automated Biometric Identification System (ABIS) , a complete ... MegaMatcher ABIS can process multiple complex biometric transactions ... of fingerprint, face or iris biometrics. It leverages ... and MegaMatcher Accelerator , which have been ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... 2016  The Prostate Cancer Foundation (PCF) is pleased to announce ... cures for prostate cancer. Members of the Class of 2016 were selected from ... Read More About the Class of 2016 PCF Young Investigators ... ... ...
(Date:6/23/2016)... ... ... Supplyframe, the Industry Network for electronics hardware design and ... in Pasadena, Calif., the Design Lab’s mission is to bring together inventors and ... brought to market. , The Design Lab is Supplyframe’s physical representation of one ...
(Date:6/23/2016)... June 23, 2016 Apellis Pharmaceuticals, Inc. ... clinical trials of its complement C3 inhibitor, APL-2. ... multiple ascending dose studies designed to assess the ... subcutaneous injection in healthy adult volunteers. ... as a single dose (ranging from 45 to ...
(Date:6/23/2016)... NEW YORK , June 23, 2016 ... the trading session at 4,833.32, down 0.22%; the Dow Jones ... the S&P 500 closed at 2,085.45, down 0.17%. has ... INFI ), Nektar Therapeutics (NASDAQ: NKTR ... BIND Therapeutics Inc. (NASDAQ: BIND ). Learn more ...
Breaking Biology Technology: