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An Overview on the Potential Antimycobacterial Agents Targeting Serine/Threonine Protein Kinases from Mycobacterium tuberculosis

Author(s):

Matteo Mori, José Camilla Sammartino, Luca Costantino, Arianna Gelain, Fiorella Meneghetti, Stefania Villa and Laurent Roberto Chiarelli  

Abstract:


Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), still remains an urgent global health issue, mainly due to the emergence of multi-drug resistant strains. Therefore, there is a pressing need to develop novel and more efficient drugs to control the disease. In this context, targeting the pathogen virulence factors, and particularly signal mechanisms, seems to be a promising approach. An important transmembrane signaling system in Mtb is represented by receptor-type Serine/Threonine protein kinases (STPKs). Mtb has 11 different STPKs, two of them, PknA and PknB, are essential. By contrast PknG and PknH are involved in Mtb virulence and adaptation, and are fundamental for the pathogen growth in infection models. Therefore, STPKs represent a very interesting group of pharmacological targets in M. tuberculosis. In this work, the principal inhibitors of the mycobacterial STPKs will be presented and discussed. In particular, medicinal chemistry efforts have been focused on discovering new antimycobacterial compounds, targeting three of these kinases, namely PknA, PknB and PknG. Generally, the inhibitory effect on these enzymes do not correlate with a significant antimycobacterial action in whole-cell assays. However, compounds with activity in the low micromolar range have been obtained, demonstrating that targeting Mtb STPKs could be a new promising strategy for the development of drugs to treat TB infections.

Keywords:

Tuberculosis, antitubercular drugs, virulence inhibition, transmembrane signal transduction, Serine/Threonine Protein Kinases, kinase inhibition.

Affiliation:

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via L. Mangiagalli 25, 20133 Milano., Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani", Università degli Studi di Pavia, via Ferrata 9, 27100 Pavia,, Dipartimento Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, via Campi 103, 41121 Modena,, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via L. Mangiagalli 25, 20133 Milano,, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via L. Mangiagalli 25, 20133 Milano,, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via L. Mangiagalli 25, 20133 Milano,, Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani", Università degli Studi di Pavia, via Ferrata 9, 27100 Pavia



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