New Clues to TB Drug Resistance

Researchers have identified the metabolic pathway used by tuberculosis bacteria to develop resistance to PA-824 and other drugs of the nitroimidazo-oxazine family.

PA-824 is a "prodrug,” it must be metabolized by the organism into an active form. Investigators at the [U.S.] National Institute of Allergy and Infectious Diseases (Bethesda, MD, USA) looked for the molecular pathway leading to PA-824 activation in Mycobacterium tuberculosis (M tb) and for an explanation as to how the bacteria develop resistance to the drug.

They began by confirming earlier data that showed that resistance derived from loss of a specific glucose-6-phosphate dehydrogenase (FGD1) or its deazaflavin cofactor F420, which together provide electrons for the reductive activation of this class of drugs. They also found that while FGD1 and F420 were necessary for sensitivity to drugs like PA-824, the activation process requires additional accessory proteins that directly interact with the drug.

To locate these proteins, the investigators worked with strains of M tb that were sensitive to PA-824 while retaining both FGD1 and F420. To rapidly scan the entire genomes of these mutant bacteria, they used a specially modified microarray-based technique, called comparative genome sequencing, developed by NimbleGen Systems, Inc. (Madison, WI, USA).

Results published in the December 30, 2005, online edition of the Proceedings of the [U.S.] National Academy of Sciences focused on four PA-824-resistant mutant strains. Two strains where found to lack a single specific protein, while the remaining two strains evidently acquired resistance to PA-824 through a mutation that made that protein unable to bind to the drug.

Finding a specific protein that interacts with the drug will allow development of a more potent form. "Previously, we were flying blind in trying to optimize PA-824 in a rational way because we did not know which M tb protein was the target of PA-824's action,” said senior author Dr.Clifton Barry III, a senior researcher in the tuberculosis section at the [U.S.] National Institute of Allergy and Infectious Diseases.




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NimbleGen Systems, Inc
National Institute of Allergy and Infectious Diseases