1887

Abstract

is uniquely susceptible to weak acids compared with other mycobacteria or bacteria. The antituberculosis activity of the front-line drug pyrazinamide (PZA), a weak acid (pyrazinoic acid) precursor, can be enhanced by inhibitors of energy metabolism and anaerobiosis. Here, we investigated the effect of inhibitors of energy metabolism and anaerobiosis on weak acid activity against in general. The susceptibility of to benzoic acid (BA) esters and amides was determined alone and in the presence of inhibitors of energy metabolism such as ,′-dicyclohexylcarbodiimide (DCCD) and azide and also under anaerobic conditions in the form of MIC and drug exposure followed by colony count. Some BA esters such as propyl hydroxybenzoic acid and 4-dodecyloxylbenzoic acid had significant activity whereas amides of BA had no activity. As for PZA, inhibitors of energy metabolism DCCD and azide enhanced the antituberculosis activity of weak acids under normal atmospheric oxygen tension. However, unlike PZA, weak acids did not show antituberculosis activity and the inhibitors of energy metabolism did not enhance the weak acid activity under anaerobic conditions. The enhancement of weak acid activity by inhibitors of energy metabolism for was not seen in other bacterial species such as . These results suggest that while the antituberculosis activity of weak acids can be enhanced by inhibitors of energy metabolism as for PZA, weak acids act differently from PZA in that they were inactive against under anaerobic conditions. The significance of these findings is discussed in the context of the unique physiology of and the development of new tuberculosis drugs.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.2008/000786-0
2008-09-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jmm/57/9/1129.html?itemId=/content/journal/jmm/10.1099/jmm.0.2008/000786-0&mimeType=html&fmt=ahah

References

  1. Christensen H., Garton N. J., Horobin R. W., Minnikin D. E., Barer M. R. 1999; Lipid domains of mycobacteria studied with fluorescent molecular probes. Mol Microbiol 31:1561–1572 [CrossRef]
    [Google Scholar]
  2. Constantino L., Rosa E., Iley J. 1992; The microsomal demethylation of N,N-dimethylbenzamides. Substituent and kinetic deuterium isotope effects. Biochem Pharmacol 44:651–658 [CrossRef]
    [Google Scholar]
  3. Raviglione M. C. 2003; The TB epidemic from 1992 to 2002. Tuberculosis (Edinb) 83:4–14 [CrossRef]
    [Google Scholar]
  4. Robinson J. R., Matheson L. E. 1969; Linear free-energy relationship between alcohol pKa and solvolysis rates of esters where substituent variation is in the alkyl portion of the ester. J Org Chem 34:3630–3633 [CrossRef]
    [Google Scholar]
  5. Schaller A., Guo M., Gisanrin O., Zhang Y. 2002; Escherichia coli genes involved in resistance to pyrazinoic acid, the active component of the tuberculosis drug pyrazinamide. FEMS Microbiol Lett 211:265–270 [CrossRef]
    [Google Scholar]
  6. Sun Z., Zhang Y. 1999a; Reduced pyrazinamidase activity and the natural resistance of Mycobacterium kansasii to the antituberculosis drug pyrazinamide. Antimicrob Agents Chemother 43:537–542
    [Google Scholar]
  7. Sun Z., Zhang Y. 1999b; Antituberculosis activity of certain antifungal and antihelmintic drugs. Tuber Lung Dis 79:319–320 [CrossRef]
    [Google Scholar]
  8. Testa B. 2004; Prodrug research: futile or fertile?. Biochem Pharmacol 68:2097–2106 [CrossRef]
    [Google Scholar]
  9. Wade M. M., Zhang Y. 2004; Anaerobic incubation conditions enhance pyrazinamide activity against Mycobacterium tuberculosis . J Med Microbiol 53:769–773 [CrossRef]
    [Google Scholar]
  10. Wade M. M., Zhang Y. 2006; Effects of weak acids, UV and proton motive force inhibitors on pyrazinamide activity against Mycobacterium tuberculosis in vitro. J Antimicrob Chemother 58:936–941 [CrossRef]
    [Google Scholar]
  11. Wade M. M., Volokhov D., Peredelchuk M., Chizhikov V., Zhang Y. 2004; Accurate mapping of mutations of pyrazinamide-resistant Mycobacterium tuberculosis strains with a scanning-frame oligonucleotide microarray. Diagn Microbiol Infect Dis 49:89–97 [CrossRef]
    [Google Scholar]
  12. Zhang Y. 2005; The magic bullets and tuberculosis drug targets. Annu Rev Pharmacol Toxicol 45:529–564 [CrossRef]
    [Google Scholar]
  13. Zhang Y., Mitchison D. 2003; The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis 7:6–21
    [Google Scholar]
  14. Zhang Y., Scorpio A., Nikaido H., Sun Z. 1999; Role of acid pH and deficient efflux of pyrazinoic acid in unique susceptibility of Mycobacterium tuberculosis to pyrazinamide. J Bacteriol 181:2044–2049
    [Google Scholar]
  15. Zhang Y., Wade M. M., Scorpio A., Zhang H., Sun Z. 2003a; Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. J Antimicrob Chemother 52:790–795 [CrossRef]
    [Google Scholar]
  16. Zhang Y., Zhang H., Sun Z. 2003b; Susceptibility of Mycobacterium tuberculosis to weak acids. J Antimicrob Chemother 52:56–60 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.2008/000786-0
Loading
/content/journal/jmm/10.1099/jmm.0.2008/000786-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error