The finding could lead to badly needed new drugs for combating tuberculosis bacteria, which each year kill an estimated 2.4 million people worldwide. The study appears in the March issue of Chemistry & Biology.

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 Vilchhze, a study co-author in Dr. Jacobs' laboratory. "The pathways that they block - fatty acid and mycolic acid synthesis and fatty acid degradation - are essential for bacterial survival, and this combined inhibition had a powerful effect against the microbes. To our knowledge, this is the first example of an antibacterial compound that inhibits several pathways to achieve its effect."

The Einstein researchers are now trying to improve on the potency of 2-HA and 2-OA by synthesizing analogues (chemically similar compounds) to them.

"We're hopeful that these new compounds will prove even more toxic to TB bacteria and could help usher in a new era of TB therapy," says Dr. Vilchhze.

aecom.yu