Bacterial Eukaryotic Type Serine-Threonine Protein Kinases: From Structural Biology to Targeted Anti-Infective Drug Design

Valery      N. Danilenko; Dmitry      I. Osolodkin; Sergey      A. Lakatosh; Maria      N. Preobrazhenskaya; Alexander      A. Shtil

Abstract

Signaling through protein kinases is an evolutionary conserved, widespread language of biological regulation. The eukaryotic type serine-threonine protein kinases (STPKs) found in normal human microbiote and in pathogenic bacteria play a key role in regulation of microbial survival, virulence and pathogenicity. Therefore, down-regulation of bacterial STPKs emerges as an attractive approach to cure infections. In this review we focused on actinobacterial STPKs to demonstrate that these enzymes can be used for crystal structure studies, modeling of 3D structure, construction of test systems and design of novel chemical libraries of low molecular weight inhibitors. In particular, the prototypic pharmacological antagonists of Mycobacterium tuberculosis STPKs are perspective for development of a novel generation of drugs to combat the socially important disease. These inhibitors may modulate both actinobacterial and host STPKs and trigger programmed death of pathogenic bacteria.

Keywords: Bacteria, Mycobacterium tuberculosis, protein kinases, classification of kinases, aminoglycoside phosphotransferase VIII, drug targets, protein kinase inhibitors, bis-indolylmaleimide, test systems, STPKs, virulence and pathogenicity, programmed death