Researchers uncover clues about how the most important TB drug attacks its target

August 13, 2014, Johns Hopkins University Bloomberg School of Public Health

Researchers at the Johns Hopkins Bloomberg School of Public Health say they have discovered a new clue to understanding how the most important medication for tuberculosis (TB) works to attack dormant TB bacteria in order to shorten treatment.

The antibiotic Pyrazinamide (PZA) has been used to treat TB since the 1950s, but its mechanisms are the least understood of all TB drugs. The PZA findings may help researchers identify new and more effective drugs not only for TB – which can require six months or more of – but other persistent bacterial infections. A report on the research is published online Aug. 13 in the journal Emerging Microbes & Infections.

"PZA is probably the most unique antibiotic we have because instead of only going after TB cells that are actively replicating, it seeks out and destroys dormant TB cells that can't be controlled by other antibiotics," says study leader Ying Zhang, MD, PhD, a professor in the Bloomberg School's Department of Molecular Microbiology and Immunology. "It's like when you're weeding. Most current drugs just chop off the leaves, but the roots are still there. PZA gets at the roots. Learning how it does that may enable us to get rid of TB quicker and more permanently without relapse."

The new study, done in conjunction with Fudan University in Shanghai, found that PZA cuts off the energy production of Mycobacterium tuberculosis, killing the bacteria. It does this by disrupting the PanD, which, among other things, is crucial to synthesis of co-enzyme A, a molecule at the center of energy metabolism. When PanD is working correctly in a TB cell, it allows the cell to survive and persist despite a long course of treatment. Only PZA's unique ability to halt this process allows it to clear the dormant bacteria.

The , who discovered another PZA target, Rspa, in recent years, say that PanD mutations are only found in a subset of TB bacteria resistant to PZA. The lab work done for the new study provides evidence that PanD is a new and distinct target for PZA, Zhang says.

PanD, Zhang says, is a promising finding because the enzyme is only present in bacteria like those found in TB and not in the cells of humans who contract the disease. It is always safer to attack a target that is only found in the dangerous organism and not in its host, he says.

In 2012, an estimated 8.6 million people worldwide developed TB and 1.3 million died from the disease. While the rate of new diagnoses is dropping, the number of drug-resistant cases is growing. When a patient is diagnosed with the lung disease, the course of treatment is six months of antibiotics. Researchers all over the world are trying to develop drugs that can work more quickly and without the toxic side effects common to all of the drugs in use.

PZA is the frontline treatment for TB. It is given to patients with both drug-susceptible and -resistant forms of the disease. All new drugs in development are used in conjunction with PZA.

Now that he understands the role that PZA plays on PanD and cells that persist long after treatment, Zhang says he plans to search for compounds that target PanD in the same way. The findings could have implications, he says, for developing drugs that target persistent organisms in other bacterial infections where dormant cells are known to re-emerge such as Lyme Disease, urinary tract infections and even cancer.

"Aspartate decarboxylase (PanD) as a new target of pyrazinamide in Mycobacterium tuberculosis" was written by Wanliang Shi, Jiazhen Chen, Jie Feng, Peng Cui, Shuo Zhang, Xinhua Weng, Wenhong Zhang, and Ying Zhang.

Explore further: Researchers identify a new mechanism of TB drug resistance

Related Stories

Researchers identify a new mechanism of TB drug resistance

June 12, 2013
Pyrazinamide (PZA)—a frontline tuberculosis (TB) drug—kills dormant persister bacteria and plays a critical role in shortening TB therapy. PZA is used for treating both drug susceptible and multi-drug resistant TB (MDR-TB) ...

Scientists establish proof-of-concept for host-directed tuberculosis therapy

June 27, 2014
In a new study published in Nature, scientists describe a new type of tuberculosis (TB) treatment that involves manipulating the body's response to TB bacteria rather than targeting the bacteria themselves, a concept called ...

New drug regimen speeds TB treatment

July 21, 2014
An experimental cocktail of three drugs can dramatically shorten the time it takes to treat patients infected with TB strains that are hard to cure with conventional antibiotics, according to research presented Monday at ...

Researchers validate preclinical effectiveness of TB drug target

November 29, 2011
In research at SRI International, scientists evaluating new drug targets against tuberculosis (TB) recently validated the preclinical effectiveness of a target that could rapidly eliminate infections and potentially shorten ...

Research reveals new drug target urgently needed for tuberculosis therapy

December 20, 2012
One third of the world is infected with the bacterium that causes tuberculosis (TB), a disease that is increasingly difficult to treat because of wide spread resistance to available drugs. Researchers from the Institute of ...

Promising class of antibiotics discovered for treatment of drug-resistant tuberculosis

March 5, 2014
St. Jude Children's Research Hospital scientists have discovered a promising new class of antibiotics that could aid efforts to overcome drug-resistance in tuberculosis (TB), a global killer. The drugs increased survival ...

Recommended for you

Onions could hold key to fighting antibiotic resistance

January 22, 2018
A type of onion could help the fight against antibiotic resistance in cases of tuberculosis, a UCL and Birkbeck-led study suggests.

New long-acting approach for malaria therapy developed

January 22, 2018
A new study, published in Nature Communications, conducted by the University of Liverpool and the Johns Hopkins University School of Medicine highlights a new 'long acting' medicine for the prevention of malaria.

Virus shown to be likely cause of mystery polio-like illness

January 22, 2018
A major review by UNSW researchers has identified strong evidence that a virus called Enterovirus D68 is the cause of a mystery polio-like illness that has paralysed children in the US, Canada and Europe.

Study ends debate over role of steroids in treating septic shock

January 19, 2018
The results from the largest ever study of septic shock could improve treatment for critically ill patients and save health systems worldwide hundreds of millions of dollars each year.

New approach could help curtail hospitalizations due to influenza infection

January 18, 2018
More than 700,000 Americans were hospitalized due to illnesses associated with the seasonal flu during the 2014-15 flu season, according to federal estimates. A radical new approach to vaccine development at UCLA may help ...

Flu may be spread just by breathing, new study shows; coughing and sneezing not required

January 18, 2018
It is easier to spread the influenza virus (flu) than previously thought, according to a new University of Maryland-led study released today. People commonly believe that they can catch the flu by exposure to droplets from ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.