One of the chemicals, 2-HA, was found to be four times more lethal than isoniazid against the bacteria, while the other, 2-OA, proved 10 times more effective. These chemically similar drugs don't appear to harm higher organisms, so they could probably be used against TB bacteria without risk to patients.
"Drug-resistant mycobacterium tuberculosis is a worldwide problem, particularly in people with weakened immune systems such as those infected with HIV," notes senior author Dr. William Jacobs, a Howard Hughes Medical Institute investigator at Einstein, as well as professor of microbiology & immunology and molecular genetics. "So we urgently need to develop new and more effective antituberculosis drugs."
Isoniazid, today's first-line anti-TB drug, stops TB bacteria from forming mycolic acid, a key building block for their cell walls. It does the job by targeting an enzyme called InhA. Trying to improve upon isoniazid, the Einstein researchers synthesized more than a dozen chemical "decoys" for InhA to latch onto, to prevent the enzyme from catalyzing its normal cell-wall-building reaction. Two of these decoy chemicals, 2-HA and 2-OA, proved much more potent than isoniazid at killing the bacteria--but not in the way the researchers expected.
"We were surprised to find that 2-HA and 2-OA were actually being metabolized in mycobacteria into two different drugs, each of which inhibits a different biochemical pathway," says Dr. Catherine Vilchze, a study co-author in Dr. Jacobs' laboratory. "The pathways that they block - fatty acid and my
Contact: Karen Gardner
Albert Einstein College of Medicine