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Knocking out salicylate biosynthesis genes in Mycobacterium smegmatis induces hypersensitivity to p-aminosalicylate (PAS)

Nagachar, Nivedita LU and Ratledge, Colin (2010) In FEMS Microbiology Letters 311(2). p.193-199
Abstract
Because of the emergence of strains of Mycobacterium tuberculosis resistant to first-line antituberculosis agents, one of the second-line drugs, p-aminosalicylate (PAS), has regained importance in the treatment of tuberculosis. The mode of action of PAS, however, remains controversial as to whether it inhibits mycobactin or folate biosynthesis. To unravel this, we have studied the effect of PAS on wild-type Mycobacterium smegmatis and its mutants (gene knockouts of the salicylate pathway - trpE2, entC and entD). The wild type had no sensitivity to PAS (MIC > 400 mu g mL-1), whereas the mutants were hypersensitive, with 1 mu g mL-1 inhibiting growth. The sulphonamides, trimethoprim and dapsone, had little effect on the growth of either... (More)
Because of the emergence of strains of Mycobacterium tuberculosis resistant to first-line antituberculosis agents, one of the second-line drugs, p-aminosalicylate (PAS), has regained importance in the treatment of tuberculosis. The mode of action of PAS, however, remains controversial as to whether it inhibits mycobactin or folate biosynthesis. To unravel this, we have studied the effect of PAS on wild-type Mycobacterium smegmatis and its mutants (gene knockouts of the salicylate pathway - trpE2, entC and entD). The wild type had no sensitivity to PAS (MIC > 400 mu g mL-1), whereas the mutants were hypersensitive, with 1 mu g mL-1 inhibiting growth. The sulphonamides, trimethoprim and dapsone, had little effect on the growth of either the mutants or the wild type. In addition, PAS at 0.5 mu g mL-1 increased the accumulation of salicylate with the wild type and mutants. These results support our hypothesis that PAS targets the conversion of salicylate to mycobactin, thus preventing iron acquisition from the host. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
salicylic acid, mycobactin, p-aminosalicylate (PAS), mycobacteria
in
FEMS Microbiology Letters
volume
311
issue
2
pages
193 - 199
publisher
Elsevier
external identifiers
  • wos:000282179400013
  • scopus:77957304787
ISSN
1574-6968
DOI
10.1111/j.1574-6968.2010.02091.x
language
English
LU publication?
no
id
f089e842-ebaf-458e-bc7f-208f546ded81 (old id 1695275)
date added to LUP
2010-10-27 13:32:14
date last changed
2018-05-29 09:20:54
@article{f089e842-ebaf-458e-bc7f-208f546ded81,
  abstract     = {Because of the emergence of strains of Mycobacterium tuberculosis resistant to first-line antituberculosis agents, one of the second-line drugs, p-aminosalicylate (PAS), has regained importance in the treatment of tuberculosis. The mode of action of PAS, however, remains controversial as to whether it inhibits mycobactin or folate biosynthesis. To unravel this, we have studied the effect of PAS on wild-type Mycobacterium smegmatis and its mutants (gene knockouts of the salicylate pathway - trpE2, entC and entD). The wild type had no sensitivity to PAS (MIC > 400 mu g mL-1), whereas the mutants were hypersensitive, with 1 mu g mL-1 inhibiting growth. The sulphonamides, trimethoprim and dapsone, had little effect on the growth of either the mutants or the wild type. In addition, PAS at 0.5 mu g mL-1 increased the accumulation of salicylate with the wild type and mutants. These results support our hypothesis that PAS targets the conversion of salicylate to mycobactin, thus preventing iron acquisition from the host.},
  author       = {Nagachar, Nivedita and Ratledge, Colin},
  issn         = {1574-6968},
  keyword      = {salicylic acid,mycobactin,p-aminosalicylate (PAS),mycobacteria},
  language     = {eng},
  number       = {2},
  pages        = {193--199},
  publisher    = {Elsevier},
  series       = {FEMS Microbiology Letters},
  title        = {Knocking out salicylate biosynthesis genes in Mycobacterium smegmatis induces hypersensitivity to p-aminosalicylate (PAS)},
  url          = {http://dx.doi.org/10.1111/j.1574-6968.2010.02091.x},
  volume       = {311},
  year         = {2010},
}