Potential therapeutic approaches for a sleeping pathogen: tuberculosis a case for bioinorganic chemistry

摘要

Mycobacterium tuberculosis (Mtb)has an old history as a human pathogen and still kills over one million people every year. One key feature of this bacterium is its dormancy: a phenomenon responsible for major changes in its metabolism and replication that have been associated with the need for a lengthy therapy for Mtb. This process is regulated by key heme-based sensors, particularly DosT and DevS (DosS), among other co-regulators, and also linked to nitrogen utilization (nitrate/nitrite) and stringent responses. In face of the current threat of tuberculosis, there is an urgent need to develop new therapeutic agents capable of targeting the dormant state, associated with the need for a lengthy therapy. Interestingly, many of those key proteins are indeed metallo-containing or metallo-dependent biomolecules, opening exciting bioinorganic opportunities. Here, we critically reviewed a series of small molecules targeting key proteins involved in these processes, including DosT/DevS/DevR, RegX3, MprA, MtrA, NarL, PknB, Rel, PPK, nitrate and nitrite reductases, GlnA1, aiming for new opportunities and alternative therapies.