Cell 155, 1296–1308 (2013)

Credit: JASON ZHANG

The intracellular pathogen Mycobacterium tuberculosis (Mtb) has numerous strategies to subvert human host bactericidal mechanisms. For instance, CD4+ T cells of the host's immune system limit the growth of Mtb. To gain more insight into the anti-pathogen effector mechanisms used by CD4+ T cells and the Mtb evasion mechanisms, Zhang et al. profiled the Mtb genome for mutants with growth defects that are rescued when CD4+ T cells are absent (in MHCII knockout mice). Growth during Mtb infection required 576 genes known as the 'counteractome', in which two biochemical pathways were highly represented, including tryptophan (Trp) biosynthesis. Experiments with Mtb mutants deleted for trpE, which catalyzes the first committed step of Trp biosynthesis, showed that Trp starvation leads to killing by the immune system and suggested that CD4+ T cells induce the requirement for Mtb Trp biosynthesis. The authors found that CD4+ T cells most likely act through IFN-γ to stimulate Trp depletion, forcing Mtb to synthesize its own Trp. They identified the fluorinated anthranilates 5-FABA and 6-FABA as inhibitors of TrpE, which were toxic to Mtb in vitro. In a mouse model of infection, a 6-FABA ester derivative effectively inhibited the growth of Mtb. These results suggest a therapeutic potential in harnessing the ability of CD4+ T cells to target Trp metabolism.