Scientists Identify Possible Cause for TB Drug Resistance

A new mechanism for pyrazinamide (PZA)-resistance a frontline tuberculosis (TB) drug has been discovered by scientists.

A new mechanism for pyrazinamide (PZA)-resistance a frontline tuberculosis (TB) drug has been discovered by Johns Hopkins Bloomberg School of Public Health and Huashan Hospital, Fudan University scientists.

PZA kills dormant persister bacteria and plays a critical role in shortening TB therapy.

Screening Tests for Tuberculosis
Tuberculin skin test and Interferon – Release Assays are tests used to screen for tuberculosis.

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.

Drug Resistance – Antibiotic or Antimicrobial Resistance
Drug resistance is often a problem in malaria, tuberculosis, HIV, sexually transmitted diseases and hospital acquired diseases. Judicious use of antibiotics can control the problem.

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 beta-alanine, a precursor for pantothenate (which is vitamin B5) and co-enzyme A biosynthesis.

Quiz on Tuberculosis
Tuberculosis is a major health care concern, especially in Africa and South East Asia. Brush up your information on tuberculosis by taking this quiz.

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.

Mortality for MDR-TB and XDR-TB Cases Could Be Reduced By TB Drug
Improved outcomes and reduced mortality among patients with both MDR-TB and XDR-TB shown by results from an observational study evaluating a new anti-TB drug.

"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," he added.

While more study is needed, Zhang and his colleagues believe panD could be a potential target for new antibiotic therapies.

The study is available online the journal Emerging Microbes and Infections.

Source-ANI