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

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 molecule as 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.

The Mycobacterial Cell Envelope--Lipids

“…Several chemical scaffolds (Vertex Pharmaceuticals Inc.) (Magnet et al 2010;Danilenko et al 2011;Lougheed et al 2011;Chapman et al 2012) 1996; Pitarque et al 2008;Dhiman et al 2011). Whether Mtb requires phosphatidylglycerol, CL, PS, and PE for growth is at present not known.…”

Extending the Interaction Repertoire of FHA and BRCT Domains

“…Although bacteria primarily rely on histidine kinases and their associated regulatory responders for phosphorylation-dependent signaling, some also utilize eukaryotic-like Ser/Thr Protein Kinases (STPKs) [56]. Like eukaryotes, bacteria can use STPKs to respond to stress, but they also participate in other processes such as pathogenicity, thereby providing important drug targets [56]. The best characterized bacterium in this regard is M. tuberculosis, the causative agent of tuberculosis, which tops the charts in the prokaryotic kingdom with eleven STPKs [57].…”

Regioselective acylation of congeners of 3-amino-1H-pyrazolo[3,4-b]quinolines, their activity on bacterial serine/threonine protein kinases and in vitro antibacterial (including antimycobacterial) activity

“…Also, some BSTK are involved in virulence of Mycobacteria and resistance of Streptomyces to aminoglycoside antibiotics 2,3 . Since it is evident that BSTK play an indispensable role in some prokaryotic organisms, these protein kinases are considered as attractive antibacterial drug targets 1,4 . It was also shown that protein kinase inhibitors of eukaryotic serine/threonine protein kinase(s) (ESTK) could be active against some BSTK 1,4,5 .…”

“…Since it is evident that BSTK play an indispensable role in some prokaryotic organisms, these protein kinases are considered as attractive antibacterial drug targets 1,4 . It was also shown that protein kinase inhibitors of eukaryotic serine/threonine protein kinase(s) (ESTK) could be active against some BSTK 1,4,5 . Several years ago, we have synthesized a combinatorial library of compounds to find inhibitors of ESTK 5 .…”

“…Several years ago, we have synthesized a combinatorial library of compounds to find inhibitors of ESTK 5 . Surprisingly, we found that some of bis-3,4-bis(indol-1-yl)maleimide analogues of known inhibitor Bis I ( Figure 1 and Table 1) are active in tests on Streptomyces lividans with overexpressed aminoglycoside phosphotransferase type VIII (aphVIII) to kanamycin by inhibiting BSTK mediated aphVIII phosphorylation 4,5 . These results correlate with the aforementioned trend.…”