JAC Advance Access published online on January 16, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh042
© 2004 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Department of Molecular Microbiology and Immunology, Bloomberg
School of Public Health, Johns Hopkins University, Baltimore, MD
21205, USA
* Corresponding author. E-mail: yzhang{at}jhsph.edu.
Received 12 September 2003
; revised 23 October 2003
; accepted 29 October 2003
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. Materials and 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.
Keywords: pyrazinamide, iron, drug susceptibility, Mycobacterium
tuberculosis
Iron enhances the antituberculous activity of pyrazinamide
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