Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis

For nearly 60 years, Pyrazinamide (PZA) has been used in conjunction with other medications to treat tuberculosis (TB), but scientists did not fully understand how the drug killed 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, published in the August 11, 2011 edition of Science Express, 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. PZA primarily kills non-growing bacteria called persisters that are not susceptible to common antibiotics," said 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. "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."

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.

"There is renewed interest in PZA because it is the only drug that cannot be replaced among the current TB drugs without compromising the efficacy of therapy. The identification of the drug target RpsA not only offers a new resistance mechanism to PZA but also opens up a way for designing a new generation of antibiotics that target persister bacteria for improved treatment of chronic and persistent infections including TB," said Zhang.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
More than 80% of patients with tuberculosis do not have persistent cough, study shows