Inducible cysteine synthesis by CysK2 provides copper resistance in Mycobacterium tuberculosis

Copper is an essential nutrient that at high levels is toxic to life. Mammalian hosts can accumulate copper in phagolysosomes to restrict a variety of pathogens, including Mycobacterium tuberculosis. However, pathogens have evolved various mechanisms to counter copper stress. While several pathways that mitigate copper-derived toxicity have been described in Mycobacterium tuberculosis, the Mycobacterium tuberculosis lab strain H37Rv is significantly more sensitive to copper than other lab strains, including CDC1551 and Erdman. Here, we determine a cause of this sensitivity in H37Rv is due to a single amino acid substitution in CysK2 (Rv0848), which is encoded in the copper-inducible RicR regulon required for robust copper resistance and virulence. H37Rv CysK2 was previously reported as a S-sulfocysteine synthase. However, we found CysK2 is a cysteine synthase, the activity of which is required for resistance to copper. This study is the first to link de novo cysteine biosynthesis with copper resistance in Mycobacterium tuberculosis.

Copper is a proposed component of the host immune response against Mycobacterium tuberculosis; thus, an understanding of how this pathogen mitigates copper stress may yield new targets for therapeutics. Cysteine synthesis is implicated in copper responses in other bacterial species, but had not been shown in mycobacterial copper resistance. This study demonstrates for the first time that the Mycobacterium tuberculosis cysteine synthase CysK2 and, by extension, cysteine biosynthesis, can promote copper resistance.