Journal
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
Volume 25, Issue 5, Pages 685-704Publisher
SPRINGER
DOI: 10.1007/s00775-020-01803-1
Keywords
Drug development; Tuberculosis; Nitrogen cycle; Kinases; Stringent response; Metalloproteins
Funding
- Associate Laboratory for Green Chemistry-LAQV - FundacAo para a Ciencia e a Tecnologia, MCTES (FCT/MCTES) [UID/QUI/50006/2019]
- CNPq [PDE 204177/2018-9, EHSS 308383/2018-4, Universal 403866/2016-2, LGFL 303355/2018-2, ICND 307078/2017-5]
- CAPES [PROEX 23038.000936/2018-46]
- FUNCAP [PRONEX PR2 0101-00030.01.00/15 SPU, 3265612/2015]
- National Institute of Science and Technology on Tuberculosis (Decit/SCTIE/MS-MCT-CNPq FNDTC-CAPES-FAPERGS) [421703/2017-2]
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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. Graphic abstract In the battle against Mycobacterium tuberculosis, new drug targets must be searched, in particular those involved in dormancy. A series of exciting cases for drug development involving metallo-containing or metallo-dependent biomolecules are reviewed, opening great opportunities for the bioinorganic chemistry community. [GRAPHICS] .
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