0000000000606385
AUTHOR
Dmitrijs Zhulenkovs
showing 4 related works from this author
Discovery and structure-activity relationship studies of irreversible benzisothiazolinone-based inhibitors against Staphylococcus aureus sortase A tr…
2014
Gram-positive bacteria, in general, and staphylococci, in particular, are the widespread cause of nosocomial and community-acquired infections. The rapid evolvement of strains resistant to antibiotics currently in use is a serious challenge. Novel antimicrobial compounds have to be developed to fight these resistant bacteria, and sortase A, a bacterial cell wall enzyme, is a promising target for novel therapies. As a transpeptidase that covalently attaches various virulence factors to the cell surface, this enzyme plays a crucial role in the ability of bacteria to invade the host's tissues and to escape the immune response. In this study we have screened a small molecule library against rec…
Discovery of a new class of sortase a transpeptidase inhibitors to tackle gram-positive pathogens: 2-(2-phenylhydrazinylidene)alkanoic acids and rela…
2016
A FRET-based random screening assay was used to generate hit compounds as sortase A inhibitors that allowed us to identify ethyl 3-oxo-2-(2-phenylhydrazinylidene)butanoate as an example of a new class of sortase A inhibitors. Other analogues were generated by changing the ethoxycarbonyl function for a carboxy, cyano or amide group, or introducing substituents in the phenyl ring of the ester and acid derivatives. The most active derivative found was 3-oxo-2-(2-(3,4dichlorophenyl)hydrazinylidene)butanoic acid (2b), showing an IC50 value of 50 µM. For a preliminary assessment of their antivirulence properties the new derivatives were tested for their antibiofilm activity. The most active compo…
Discovery of a New Class of Sortase A Transpeptidase Inhibitors to Tackle Gram-positive Pathogens: 2-Phenylhydrazonoalkanoic Acid Derivatives
2015
There is an urgent need of anti-virulence agents effective in the prevention or eradication of biofilms that are intrinsically resistant to conventional antibiotics. If we consider that the first step of staphylococcal pathogenesis and of biofilm formation is the bacterial adhesion, promoted by the surface exposed proteins at the cell wall, we believe that new anti-virulence agents could be developed by using as a target the Sortase A (SrtA), the enzyme responsible of linking surface exposed proteins to peptidoglycan. Therefore, SrtA inhibitors could act as anti-adhesion agents useful to prevent Gram positive virulence mechanisms as well as a virulence mechanism based on biofilm formation. …
Enzymatic activity of circular sortase A under denaturing conditions: An advanced tool for protein ligation
2014
Abstract Staphylococcus aureus sortase A is a transpeptidase that is extensively used in various protein research applications. Sortase A is highly selective and does not require any cofactors for the catalysis of protein ligation and, importantly, can be produced in high yields. However, the primary disadvantage of this transpeptidase is its inability to access the recognition site within the highly structured regions of folded substrates. To overcome this problem, we developed an Escherichia coli expression system that produces milligram quantities of circularly closed sortase A; efficient enzyme cyclization was achieved by Synechocystis sp. PCC6803 intein-mediated post-translational spli…