Iron acquisition pathways as targets for antitubercular drugs

Fiorella Meneghetti, Stefania Villa, Arianna Gelain, Daniela Barlocco, Laurent Roberto Chiarelli, Maria Rosalia Pasca, Luca Costantino

Research output: Contribution to journalArticlepeer-review


Tuberculosis nowadays ranks as the second leading cause of death from an infectious disease worldwide. In the last twenty years, this disease has again started to spread mainly for the appearance of multi-drug resistant forms. Therefore, new targets are needed to address the growing emergence of bacterial resistance and for antitubercular drug development. Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis, because it serves as cofactor in many essential biological processes, including DNA biosynthesis and cellular respiration. Bacteria acquire iron chelating non-heme iron from the host using the siderophore mycobactins and carboxymycobactins and by the uptake of heme iron released by damaged red blood cells, through several acquisition systems. Drug discovery focused its efforts on the inhibition of MbtI and MbtA, which are are two enzymes involved in the mycobactin biosynthetic pathway. In particular, MbtI inhibitors have been studied in vitro, while MbtA inhibitors showed activity also in infected mice. Another class of compounds, MmpL3 inhibitors, showed antitubercular activity in vitro and in vivo, but their mechanism of action seems to be off-target. Some compounds inhibiting 4′-phosphopantetheinyl transferase were discovered but not tested on in vivo assays. The available data reported in this study based on inhibitors and gene deletion studies, suggest that targeting iron acquisition systems could be considered a promising antitubercular strategy. Due to their redundancy, the relative importance of each pathway for Mycobacterium tuberculosis survival has still to be determined. Thus, in vivo studies with new, potent and specific inhibitors are needed to highlight target selection.

Original languageEnglish
Pages (from-to)4009-4026
Number of pages18
JournalCurrent Medicinal Chemistry
Issue number35
Publication statusPublished - Oct 1 2016


  • (Iso)chorismate analogs
  • Enzymatic inhibition
  • Iron chelators
  • Mycobactin biosynthesis
  • Siderophore
  • Tuberculosis

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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