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

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Abstract

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.

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Abbreviations

DosT:

Histidine kinase sensor of the oxygen-responsive two-component system (DevS/DosT/DevR)

DevS(DosS):

Histidine kinase sensor of the oxygen-responsive two-component system (DevS/DosT/DevR)

DevR(DosR):

Response regulator of the oxygen-responsive two-component system (DevS/DosT/DevR)

RegX3:

Response regulator of the two-component system (SenX3/RegX3)

MprA:

Response regulator of the two-component system (MprB/MprA)

MtrA:

Response regulator of the two-component system (MtrB/MtrA)

NarL:

Response regulator of a nitrite-responsive two-component system (NarS/NarL)

PknB:

Serine and threonine kinase

Rel:

(p)ppGpp synthase and phosphatase enzyme

PPK:

Polyphosphate kinase

Nar:

Nitrate reductase

Nir:

Nitrite reductase

GlnA1:

Glutamine synthetase

SAR:

Structure–activity relationship

QSAR:

Quantitative structure–activity relationship

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Acknowledgements

This work was supported by the Associate Laboratory for Green Chemistry-LAQV, which is financed by national funds from Fundacão para a Ciência e a Tecnologia, MCTES (FCT/MCTES; UID/QUI/50006/2019). We are also thankful to CNPq (PDE 204177/2018-9, EHSS 308383/2018-4, Universal 403866/2016-2, LGFL 303355/2018-2, and and ICND 307078/2017-5), CAPES (PROEX 23038.000936/2018-46), FUNCAP (PRONEX PR2 0101-00030.01.00/15 SPU Nº: 3265612/2015) and National Institute of Science and Technology on Tuberculosis (Decit/SCTIE/MS-MCT-CNPq FNDTC-CAPES-FAPERGS, grant number 421703/2017-2) for financial support. In addition, we are thankful to Dr. Marie-Alda Gilles-Gonzalez (University of Texas Southwestern Medical Center, USA) for suggestions and assistance on English proofreading.

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  1. Laboratório de Bioinorgânica, Departamento de Química Orgânica E Inorgânica, Universidade Federal Do Ceará, Fortaleza, Ceará, Brazil

    Eduardo H. S. Sousa, Izaura C. N. Diógenes & Luiz G. F. Lopes

  2. Instituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil

    Eduardo H. S. Sousa & Luiz G. F. Lopes

  3. LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal

    José J. G. Moura

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  1. Eduardo H. S. Sousa
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Sousa, E.H.S., Diógenes, I.C.N., Lopes, L.G.F. et al. Potential therapeutic approaches for a sleeping pathogen: tuberculosis a case for bioinorganic chemistry. J Biol Inorg Chem 25, 685–704 (2020). https://doi.org/10.1007/s00775-020-01803-1

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