Identification of novel mutations in LprG (rv1411c), rv0521, rv3630, rv0010c, ppsC, cyp128 associated with pyrazinoic acid/pyrazinamide resistance in Mycobacterium tuberculosis

Wanliang Shi, Jiazhen Chen, Shuo Zhang, Wenhong Zhang, Ying Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

There is currently considerable interest in understanding the mechanisms of action of pyrazinamide (PZA), a critical frontline tuberculosis (TB) drug that plays a unique role in shortening TB therapy due to its unique activity against Mycobacterium tuberculosis persisters that are not killed by other TB drugs.1,2 Despite the importance of PZA in the treatment of both drug susceptible and drug-resistant TB and its simple structure, its mechanisms of action are complex and are not well understood.1,2 PZA is a prodrug that is converted to the active form pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase) encoded by the pncA gene,3 whose mutation is the most common mechanism of PZA resistance in M. tuberculosis.3-5 However, some low level PZA-resistant strains (MIC=200-300 μg/ml, pH6.0) do not have mutations in the pncA gene.5,6 Recent studies have identified rpsA, which encodes the ribosomal protein S1 involved in both translation and trans-translation process, as a target of PZA,7 where its mutations are associated with PZA resistance from clinical isolates. In addition, mutations in panD encoding aspartate decarboxylase were identified as a new mechanism of PZA resistance from in vitro mutants resistant to PZA and the PanD protein was found to be another target of PZA.8,9 panD mutations were initially found in mutants resistant to PZA 8 and then in mutants resistant to POA. 9,10 It is worth noting that previously POA-resistant mutants could not be isolated at acid pH which is required for higher activity of PZA against M. tuberculosis. However, we were able to successfully isolate POA-resistant mutants with high POA concentrations at close to neutral pH (pH 6.8),9 which led to discovery of new genes involved in POA and PZA resistance. For example, clpC1, which was also isolated from mutants resistant to PZA,11 was identified in mutants resistant to POA.12

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Jan 17 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Fingerprint Dive into the research topics of 'Identification of novel mutations in LprG (rv1411c), rv0521, rv3630, rv0010c, ppsC, cyp128 associated with pyrazinoic acid/pyrazinamide resistance in Mycobacterium tuberculosis'. Together they form a unique fingerprint.

Cite this