title: Iron enhances the antituberculous activity of pyrazinamide.
abstract: BACKGROUND
  Pyrazinamide is a paradoxical frontline tuberculosis drug characterized by high in vivo sterilizing activity but poor in vitro activity. This separation in pyrazinamide activity reflects differences between the in vivo tissue environment and in vitro culture conditions. The well-known acid pH requirement for pyrazinamide activity was discovered previously based on such reasoning but does not completely explain the discrepancy between in vivo and in vitro activity of pyrazinamide. This study examined the effect of iron, which could potentially be elevated in local inflammatory lesions, on pyrazinamide activity in vitro.
  
  
  METHODS
  The effect of iron on the activity of pyrazinamide or its active derivative pyrazinoic acid against Mycobacterium tuberculosis was assessed in liquid medium in a drug exposure assay or in solid medium with pyrazinamide plus iron or pyrazinamide alone. The effect of iron on pyrazinamide or pyrazinoic acid was expressed as percentage of growth inhibition.
  
  
  RESULTS
  We have shown that iron enhances the activity of pyrazinamide and pyrazinoic acid against M. tuberculosis in both liquid and solid media at acid pH 5.6. Iron enhanced the activity of pyrazinoic acid but not pyrazinamide against the naturally pyrazinamide-resistant Mycobacterium bovis BCG. Other metal ions such as magnesium, calcium and zinc did not enhance the activity of pyrazinamide or pyrazinoic acid.
  
  
  CONCLUSIONS
  Iron increased the activity of pyrazinamide or pyrazinoic acid against M. tuberculosis in vitro. These findings may have implications for the study of mechanism of action of pyrazinamide and possible iron supplement for improving the activity of pyrazinamide.
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. yzhang@jhsph.edu
authors.forename: Akos
authors.initials: A
authors.lastname: Somoskovi
authors.forename: Mary Margaret
authors.initials: MM
authors.lastname: Wade
authors.forename: Zhonghe
authors.initials: Z
authors.lastname: Sun
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D003470:Culture Media; D004357:Drug Synergism; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015032:Zinc / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D003470:Culture Media; D011718:Pyrazinamide; C005296:pyrazinoic acid; D007501:Iron; D008274:Magnesium; D015032:Zinc; D002118:Calcium