Researchers target virulence factors (5/4/2008)

For more than six decades, doctors have been waging war against infectious bacterial illness with antibiotics, the best weapon they have. But they are losing ground as more strains of tuberculosis and other potentially fatal infections become resistant to multiple antibiotics.

Now, researchers from Weill Cornell Medical College (WCMC) say there is an alternative, potent way to treat tuberculosis, Hansen's disease (leprosy) and other bacteria-caused illnesses: by inhibiting molecular targets -- the so-called "virulence factors" that help bacteria thrive once they are in the host.

The researchers have developed the first inhibitor of a key small molecule from Mycobacterium tuberculosis, which subverts the human host's defenses, and M. leprae (which causes leprosy), which damages the host's cells during infection.

"With this work, we now have proof of principle for the inhibition of this virulence factor in bacteria cultured in the lab," said lead researcher Luis Quadri, associate professor of microbiology and immunology at WCMC. "Our next step is to explore whether this inhibitor can stop these pathogens from multiplying in a mouse host, curtailing infection."

The findings, published recently in the journal Chemistry and Biology, highlight what Quadri called a "paradigm shift" in infectious disease research.

"We are moving beyond anti-microbials 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 said. "We believe that the expansion of the drug armamentarium to include such anti-infective drugs could help the fight against multidrug-resistant infection that has become such a challenge today."

Tuberculosis is among the 10 leading causes of death globally, killing nearly 2 million people annually. Multidrug resistant strains of M. tuberculosis -- as well as even more dangerous, extensive-drug-resistant strains of the bug -- are emerging each year.

"Obviously, we are going to require more than the traditional anti-microbial approach to turn this situation around," Quadri said.

In the latest study, Quadri, with co-lead researchers Julian Ferraras and Karen Stirrett, focused on particular small-molecule virulence factors called phenolic glycolipids (PGLs), which are used by various strains of M. tuberculosis to weaken the body's defenses and by M. leprae to damage and invade nerve cells during infection.

The researchers hypothesized that drugs blocking PGL synthesis would reduce their impairing effects on the host system. To test the idea, they pinpointed a key enzyme, called FadD22, that is essential to PGL synthesis. Working with Memorial Sloan-Kettering Cancer Center researcher Derek Tan, they synthesized a molecule that targets FadD22.

Follow-up work 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 under way to come up with other, even more potent PGL biosynthesis inhibitors, with an eye to testing the best candidates in an animal model, said Quadri.

"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," Quadri said, noting that the findings are highly encouraging.

"Drugs targeting virulence factors ... will offer patients more options in the fight against truly global killers," he said.

The research was funded by the National Institutes of Health; the Stavros S. Niarchos Foundation; New York State Foundation for Science, Technology and Innovation Watson Investigator Program; William H. Goodwin and Alice Goodwin; the Commonwealth Foundation for Cancer Research; and Memorial Sloan-Kettering Cancer Center Experimental Therapeutics Center.

Ernie Mundell is a freelance writer in New York.

Note: This story has been adapted from a news release issued by Cornell University

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