Bacterial protein kinase inhibitors

Abstract

Protein kinases have become the second most important group of drug targets for the pharmaceutical industry next to G-protein-coupled receptors. Thus, over the past decade, a significant number of small molecules have been generated for protein kinase drug optimization programs. The vast majority of kinase inhibitors target the ATP binding site of the enzyme; however, the poor protein kinase selectivity of ATP-competitive protein kinase inhibitors (PKIs) limits their use for treating chronic diseases. In contrast, for inhibitors of bacterial signal transduction systems targeting bacterial kinase(s), there are no such selectivity requirements as long as the inhibitor does not act on any human kinases at the effective concentrations for killing bacteria in vivo. Protein phosphorylation in bacteria is performed by twocomponent signal transduction systems (2CSTSs) and eukaryotic-like serine/threonine kinases or bacterial tyrosine kinases. Recently, a large number of studies of protein kinases essential for sustaining bacterial growth and kinases required for virulence have been reported. Thus, bacterial protein kinases offer considerable potential as new drug targets. To identify bacterial PKIs, large chemical libraries of ATPcompetitive inhibitors developed for eukaryotic protein kinases are an invaluable asset. This manuscript reviews progress on the development of prokaryotic protein kinase inhibitors. Drug Dev Res 71:168-187, 2010.

Regulation of transcription by eukaryotic-like serine-threonine kinases and phosphatases in Gram-positive bacterial pathogens

“…In this regard, the future advancement of the field of prokaryotic PTMs will also be discussed, as a better understanding of these signaling systems will shed light on how eSTK/Ps empower bacteria to cause a range of infections in most important pathogens, and could ultimately offer a realistic focal point of therapeutic strategies in disease prevention. [74][75][76][77]146 Transcription Factors Regulated by eSTKs and eSTPs…”

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

“…It was found that congeners of pyrazolo [2,3-b] quinoline have inhibitory activity on several ESTK from several species with wide ranging activity and relatively low specificity. For example, CID 665826 (1) and related compounds reveal inhibitory activity on GSK-3, CDK and ATM kinases 6 . Compound 2 built on the 1H-pyrazolo [3,4-b]pyridine fragment showed inhibition on disease-relevant protein kinases DYRK1A, CDK5 and GSK 7 .…”

“…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 .…”

“…BSTK are necessary in most important steps of bacterial pathogenesis 1 . Also, some BSTK are involved in virulence of Mycobacteria and resistance of Streptomyces to aminoglycoside antibiotics 2,3 .…”