EXPRESSION, BIOCHEMICAL CHARACTERIZATION AND STRUCTURAL STUDIES OF POLYSACCHARIDE MODYFING ENZYMES OF THE CELL WALL OF OF PATHOGENIC BACTERIA AND DESIGN OF INHIBITORS WITH ANTIBACTERIAL ACTION

Abstract: 

The development of new antibacterial agents to combat worsening antibiotic resistance is a priority area in anti-infectives research. In contrast to bacterial cell wall biosynthesis which is a well established target for antibacterial chemotherapy, there is limited information on peptidoglycan and other bacterial polysaccharide modifying enzymes. Although humans possess glycosidases such as lysozymes (targeting peptidoglycan in the bacterial cell wall) as part of their innate immune system, it is becoming increasingly clear that bacteria may evade these lytic enzymes by (partially) de-N-acetylating N-acetylglucosamine residues or O-acetylating N-acetylmuramic and N-acetylglucosamine residues of their cell wall peptidoglycan.

The genomes of Bacillus cereus and its closest relative Bacillus anthracis contain 11 polysaccharide deacetylase homologues. Six of these homologues have been proposed to be peptidoglycan N-acetylglucosamine deacetylases. The unusual occurrence of multiple putative deacetylases in Bacillus sp. (and more specifically in B.cereus and B.anthracis) possibly indicates the different roles of these enzymes e.g. in sporulation, spore germination, vegetative growth and host' microbe interactions. Alternatively, these enzymes could modify other cell wall polysaccharides. A new cluster of genes consisting of an O-acetyltransferase (pat) gene and at least one O-acetyl esterase (ape) gene has been identified in a number of pathogenic bacteria including Helicobacter pylori.

The main aim of this proposal is to characterize the enzymes responsible for peptidoglycan modification in terms of structure and function and to develop possible strategies of inhibition of these enzymes. This will capitalize on some exciting recently obtained preliminary data. Specifically we will target the putative peptidoglycan N-deacetylases from B.anthracis and O-acetyltramsferases/esterases from H.pylori.

Project info

Acronym:
INTAHUPA, Inhibition of New TArgets of HUman PAthogens
Coordinating Institution:
University of Crete
Scientific Coordinator:
Bouriotis Vassilis
Research Team 2 Leader:
Eliopoulos Elias
Research Team 3 Leader:
Tzartos Socrates

Stats

I.D.:
62
Mis:
377288
Duration (months):
43
Budget:
600 000.00
Diavgeia:
ΑΔΑ: Β4ΛΔ9-ΩΤΡ

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