Toxicity of the iron siderophore mycobactin J in mouse macrophages: Evidence for a hypoxia response

Mycobacterium tuberculosis, the causative agent of tuberculosis, is an obligate intracellular pathogen that lives within the phagosome of macrophages. Here we demonstrate that the siderophore mycobactin J, produced by the closely related intracellular pathogen Mycobacterium paratuberculosis, is toxic to murine macrophage cells. Its median lethal dose, 10 μM, is lower than that of the iron chelators desferrioxamine B and TrenCAM, an enterobactin analog. To determine the source of this toxicity, we conducted microarray, ELISA, and metabolite profiling experiments. The primary response is hypoxia-like, which implies iron starvation as the underlying cause of the toxicity. This observation is consistent with our recent finding that mycobactin J is a stronger iron chelator than had been inferred from previous studies. Mycobactin J is known to partition into cell membranes and hydrophobic organelles indicating that enhanced membrane penetration is also a likely factor. Thus, mycobactin J is shown to be toxic, eliciting a hypoxia-like response under physiological conditions.