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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Nivedita Nagachar
  • Colin Ratledge
External organisations
  • University of Hull
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology
  • Surgery

Keywords

  • salicylic acid, mycobactin, p-aminosalicylate (PAS), mycobacteria
Original languageEnglish
Pages (from-to)193-199
JournalFEMS Microbiology Letters
Volume311
Issue number2
Publication statusPublished - 2010
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes