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How drug critical in treating tuberculosis kills bacteria

August 12, 2011 - Washington

Scientists have conducted a study on how critical drug Pyrazinamide (PZA) works with other medications to kill TB bacteria.

PZA plays a unique role in shortening the duration of current TB therapy to six months and is used frequently to treat multi-drug resistant TB.

A new study, led by researchers at the Johns Hopkins Bloomberg School of Public Health, suggests that PZA binds to a specific Protein named RpsA and inhibits trans-translation, a process that enables the TB bacteria to survive under stressful conditions.

Their findings, could lead to new targets for developing more effective anti-TB drugs.

"PZA is a peculiar and unconventional drug that works very differently from common Antibiotics that mainly kill growing bacteria," Ying Zhang, MD, PhD, senior author of the study and professor in the Bloomberg School's W. Harry Feinstone Department of Molecular Microbiology and Immunology, said.

"PZA primarily kills non-growing bacteria called persisters that are not susceptible to common Antibiotics.

"While PZA works very well in the body against TB, it has no effect on the growing bacteria in a test tube, which has made it difficult to understand just how it works," Zhang said.

PZA is converted to the active form of pyrazinoic acid (POA) by an amidase enzyme (PncA) also identified by Zhang's group in 1996.

Through a series of experiments, Zhang and his colleagues determined that POA binds to ribosomal Protein S1 (RpsA), a vital protein in the trans-translation process.

Trans-translation is essential for cell survival under stress conditions. Partially synthesized Proteins, which are produced under stress conditions, are toxic to the bacterial cell.

It has developed a mechanism called trans-translation to add a short peptide tag to the partially produced toxic Proteins so they can be recognized for degradation by proteases to relieve the toxicity.

Inhibition of trans-translation by PZA explains why the drug can eradicate persisting organisms, and thereby shortening the therapy.

The findings have been published in the August 11, 2011 edition of Science Express.


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