Fighting Bacterial Infections in Novel Ways

A new study has found that molecular targets--"virulence factors” that bacteria use to thrive once they are in the host--present an alternative, potent means of stopping tuberculosis (TB), leprosy, and other bacterial illness.

Researchers from the Weill Cornell Medical College (New York, NY, USA) and Memorial Sloan-Kettering Cancer Center (New York, NY, USA) hypothesized that drugs blocking phenolic glycolipid (PGL; a small-molecule virulence factor) biosynthesis would reduce the adaptive fitness of PGL-producing Mycobacterium tuberculosis strains in the human host, by eliminating PGL-dependent immunomodulatory effects. The researchers then pinpointed a key enzyme, called FadD22, essential to that stage of the biosynthesis process. In the next step, they created a molecule that targets FadD22, successfully inhibiting that early step in PGL production. 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, the researchers believe their agent would inhibit production of PGLs there, as well. Research is also underway to come up with other, even more potent PGL biosynthesis inhibitors, with an eye to testing the best candidates in an animal model. The study was published on December 22, 2007, in the online version of the journal Chemistry and Biology.

"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,” said senior author Dr. Luis Quadri, an associate professor of microbiology and immunology at Weill Cornell. "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.”

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


Related Links:
Weill Cornell Medical College
Memorial Sloan-Kettering Cancer Center