(Press-News.org) 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) but resistance to PZA occurs frequently and can compromise treatment.
A recent study, led by researchers at the Johns Hopkins Bloomberg School of Public Health and Huashan Hospital, Fudan University, has identified a new mechanism for PZA-resistance, which provides new insight into the how this mysterious drug works. The study is available online June 12 in the journal Emerging Microbes and Infections.
Previously, the Johns Hopkins group identified mutations in the pncA gene and the rpsA gene as the primary causes for PZA resistance. According to the study authors, resistance to PZA is most commonly caused by mutations in the pncA gene encoding enzyme nicotinamidase/pyrazinamidase, which converts the prodrug PZA to the active form pyrazinoic acid (POA), and sometimes associated with mutations in the drug target RpsA (ribosomal protein S1). The active form of PZA, POA, interacts chemically with RpsA to block the trans-translation process, which is essential for bacterium's survival under stress conditions.
However, for unknown reasons, some PZA-resistant TB bacteria lack mutations in pncA or rpsA. The current study suggests that mutations in the panD gene may also be involved. PanD encodes aspartate decarboxylase, which is involved in synthesis of the amino acid β-alanine, a precursor for pantothenate (which is vitamin B5) and co-enzyme A biosynthesis. The panD mutations were identified not only in mutants isolated from in vitro but also in clinical isolates such as in the naturally PZA-resistant bacterium M. canettii strain and in a PZA-resistant MDR-TB strain.
"There is significant recent interest in understanding PZA, since it is the only TB drug that cannot be replaced without compromising the efficacy of the therapy. It's indispensible," 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. "The process of identifying the correct resistance mutations was quite tedious and took about two years to complete. However, the work led to the identification of a potential new mechanism of PZA resistance."
While more study is needed, Zhang and his colleagues believe panD could be a potential target for new antibiotic therapies.
The study was conducted in collaboration with researchers Wenhong Zhang and Jiazhen Chen from Fudan University. The authors of "Mutations in panD encoding aspartate decarboxylase are associated with pyrazinamide resistance in Mycobacterium tuberculosis" are Shuo Zhang, Jiazhen Chen, Wanliang Shi, Wei Liu, Wenhong Zhang, and Ying Zhang.
###
Funding for the research was provided by the National Institute for Allergy and Infectious Diseases, National Institutes of Health, and the Major Project of the Twelfth Five-Year Plan, China.
Researchers identify a new mechanism of TB drug resistance
2013-06-12
ELSE PRESS RELEASES FROM THIS DATE:
Public health's role in health care reform -- Lessons from Massachusetts
2013-06-12
Philadelphia, Pa. (June 12, 2013) – How will full implementation of the Affordable Care Act (ACA) affect the work and goals of state and local public health departments—and how can public health personnel contribute to the success of health care reform? The experience in Massachusetts has some important lessons, according to an article published online by the Journal of Public Health Management and Practice. The journal is published by LWW is part of Wolters Kluwer Health.
Just as Massachusetts was implementing its ground-breaking health care reform legislation, John ...
People anticipate others' genuine smiles, but not polite smiles
2013-06-12
Smile and the world smiles with you — but new research suggests that not all smiles are created equal. The research shows that people actually anticipate smiles that are genuine but not smiles that are merely polite. The differing responses may reflect the unique social value of genuine smiles.
"These findings give us the first clear suggestion that the basic processes that guide responses to reward also play a role in guiding social behavior on a moment-to-moment basis during interactions," explains psychological scientist and lead researcher Erin Heerey of Bangor University ...
World Oceans Month brings mixed news for oysters
2013-06-12
In World Oceans Month, there's mixed news for the Pacific Northwest oyster industry.
For the past several years, it has struggled with significant losses due to ocean acidification. Oyster larvae have had mortality rates high enough to render production no longer economically feasible.
Now a new study documents why oysters appear so sensitive to increasing acidity, but also offers some hope for the future.
It isn't necessarily a case of acidic water dissolving the oysters' shells, scientists say. It's water high in carbon dioxide altering shell formation rates, energy ...
New study finds less than 25 percent of new doctors work in primary care
2013-06-12
WASHINGTON, DC (June 12, 2013)— Despite a critical shortage of primary care in the United States less than 25 percent of newly minted doctors go into this field and only a tiny fraction, 4.8 percent, set up shop in rural areas, according to a study by researchers at the George Washington University School of Public Health and Health Services (SPHHS). Those findings, from a report just released in the "Published Ahead-of-Print" section in Academic Medicine, suggest the nation's output of primary care physicians falls short of a demonstrated need and will be unable to solve ...
Resilience in trying times -- a result of positive actions
2013-06-12
Communities that stick together and do good for others cope better with crises and are happier for it, according to a new study by John Helliwell, from the University of British Columbia in Canada, and colleagues¹. Their work suggests that part of the reason for this greater resilience is the fact that humans are more than simply social beings, they are so-called 'pro-social' beings. In other words, they get happiness not just from doing things with others, but from doing things both with and for others. The paper² is published online in Springer's Journal of Happiness ...
Moving iron in Antarctica
2013-06-12
The seas around Antarctica can, at times, resemble a garden. Large-scale experiments where scientists spray iron into the waters, literally fertilizing phytoplankton, have created huge man-made algal blooms. Such geoengineering experiments produce diatoms, which pull carbon dioxide out of the air. Experts argue that this practice can help offset Earth's rising carbon dioxide levels. However, the experiments are controversial and, according to a new study at the Georgia Institute of Technology, perhaps not as effective as expected.
Georgia Tech research published online ...
University of Toronto breakthrough allows fast, reliable pathogen identification
2013-06-12
U of T Breakthrough Allows Fast, Reliable Pathogen Identification
TORONTO, ON – Life-threatening bacterial infections cause tens of thousands of deaths every year in North America. Increasingly, many infections are resistant to first-line antibiotics. Unfortunately, current methods of culturing bacteria in the lab can take days to report the specific source of the infection, and even longer to pinpoint the right antibiotic that will clear the infection. There remains an urgent, unmet need for technologies that can allow bacterial infections to be rapidly and specifically ...
Do parasites upset food web theory?
2013-06-12
Parasites comprise a large proportion of the diversity of species in every ecosystem. Despite this, they are rarely included in analyses or models of food webs. If parasites play different roles from other predators and prey, however, their inclusion could fundamentally alter our understanding of how food webs are organized. In a paper published 11 June in the open access journal PLOS Biology, Santa Fe Institute Professor Jennifer Dunne and her team test this assertion and show that including parasites does alter the structure of food webs, but that most changes occur because ...
Walking or cycling to work linked to healthier weight in India
2013-06-12
People in India who walk or cycle to work are less likely to be overweight or obese, according to a study led by Christopher Millett from Imperial College London and the Public Health Foundation of India and colleagues. Their paper reporting the study, published in this week's PLOS Medicine, reveals that cyclists are also less likely to have diabetes or high blood pressure compared to people who take public or private transport to work.
These findings are important as they suggest that active travel could reduce rates of important risk factors for many chronic diseases, ...
Low-and middle-income countries need to prioritize noncommunicable disease prevention
2013-06-12
Nine years after the World Health Organization adopted a global strategy on diet, physical activity, and health to address risk factors for chronic diseases such as heart disease and diabetes (referred to internationally as noncommunicable diseases), only a few low-and middle-income countries have implemented robust national policies to help prevent such diseases, according to a study by international researchers published in this week's PLOS Medicine.
These findings are important as they suggest that the majority of the world's low- and middle-income countries are not ...