ACS Chem. Biol. 10.1021/acschembio.5b00517

The difficulty of targeting dormant Mycobacterium tuberculosis (Mtb) strains remains an obstacle in tuberculosis (TB) treatment. One potential strategy is to impair the bacteria's ability to cope with elevated levels of reactive oxygen species (ROS). The sulfate assimilation pathway utilizes inorganic sulfate to produce reduced sulfur metabolites, such as cysteine and the antioxidant mycothiol, to deal with increased oxidative stress. The first step of this pathway is mediated by APS reductase (APSR), which presents a potential target for therapeutics given that Mtb CysH mutant strains, which lack APSR activity, show reduced virulence in a mouse model of TB. Palde et al. have designed a high-throughput screen using a luminescent reporter to identify inhibitors of APSR activity. They focused on analogs of the plant alkaloid ellipticine, which had strong bactericidal activity against non-replicating wild-type and multi-drug-resistant clinical isolates due to increased oxidative stress. Unlike ellipticine, these derivatives did not form DNA adducts and were nontoxic to mammalian cells at bactericidal concentrations. Palde et al. confirmed the on-target activity of these compounds by demonstrating a lack of responsiveness in CysH mutant strains and showing that compound treatment decreased the production of downstream metabolites such as cysteine and mycothiol. Overall, given that APSR lacks a human homolog, these findings offer a new therapeutic avenue for the treatment of persistent and drug-resistant tuberculosis.