New drug targets to fight tuberculosis, other bacterial infections identified

December 28th, 2007 - 5:41 pm ICT by admin  

Washington , Dec 28 (ANI): Researchers from Weill Cornell Medical College in New York City , have moved beyond using antibiotics for treating tuberculosis, by finding new drug targets that may fight the disease and other bacterial infections in a novel way.

It was suggested by researchers that exciting new molecular targets known as “virulence factors” used by bacteria to thrive once they are in the host, present an alternative, potent means of stopping TB, leprosy and other bacterial illness.

The study was led by Dr. Luis Quadri, Associate Professor of Microbiology and Immunology at Weill Cornell.

“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,” he said.

He added: “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.

According to Dr.Quadri, the studys findings highlight 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 explained.

During the study, the researchers primary focus was on particular small-molecule virulence factors called phenolic glycolipids (PGLs).

While, PGLs are used by various strains of M. tuberculosis in order to weaken our body defenses, they are used by M. leprae 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 said.

The researchers investigated and revealed an important early step in PGL biosynthesis.

They also identified a key enzyme, called FadD22 that is essential to that stage of the process.

The fact that the new inhibitor blocks the production of PGLs was confirmed when both enzyme assays and M. tuberculosis assays were used in the follow-up work.

Dr.Quadri said that the work is already underway to come up with other, even more potent PGL biosynthesis inhibitors, 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,” said Dr. Quadri.

He added that the new discoveries are highly encouraging.

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

The study is published online in the journal Chemistry and Biology. (ANI)

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