Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Identify a New Mechanism of TB Drug Resistance

13.06.2013
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) 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 â-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.

Johns Hopkins Bloomberg School of Public Health media contact: Tim Parsons at 410-955-7619 or tmparson@jhsph.edu.

Johns Hopkins Bloomberg School of Public Health
615 N. Wolfe Street, Baltimore, MD 21205
Contact Us Directions & Maps Calendars Offices &
Services Online Learning &
Courses Careers Accreditation Web Policies Feedback

Tim Parsons | EurekAlert!
Further information:
http://www.jhsph.edu

More articles from Life Sciences:

nachricht Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover

nachricht First transcription atlas of all wheat genes expands prospects for research and cultivation
17.08.2018 | Leibniz-Institut für Pflanzengenetik und Kulturpflanzenforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Color effects from transparent 3D-printed nanostructures

New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

LaserForum 2018 deals with 3D production of components

17.08.2018 | Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

 
Latest News

Smallest transistor worldwide switches current with a single atom in solid electrolyte

17.08.2018 | Physics and Astronomy

Robots as Tools and Partners in Rehabilitation

17.08.2018 | Information Technology

Climate Impact Research in Hannover: Small Plants against Large Waves

17.08.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>