Reference : New noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant b...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
New noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria.
Turk, Samo [> > > >]
Verlaine, Olivier mailto [Université de Liège - ULiège > > Centre d'ingénierie des protéines]
Gerards, Thomas mailto [Université de Liège - ULiège > > Labo de Bioénergétique]
Zivec, Matej [> > > >]
Humljan, Jan [> > > >]
Sosic, Izidor [> > > >]
Amoroso, Ana Maria mailto [Université de Liège - ULiège > > Centre d'ingénierie des protéines]
Zervosen, Astrid mailto [Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse]
Luxen, André mailto [Université de Liège - ULiège > Département des sciences de la vie > Physiologie et génétique bactériennes]
Joris, Bernard mailto [> > > >]
Gobec, Stanislav [ > > ]
PloS one
Yes (verified by ORBi)
United States
[en] BACKGROUND: Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs beta-lactams inhibit transpeptidase activity of PBPs by forming a covalent penicilloyl-enzyme complex that blocks the normal transpeptidation reaction; this finally results in bacterial death. In some resistant bacteria the resistance is acquired by active-site distortion of PBPs, which lowers their acylation efficiency for beta-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs. METHODOLOGY/PRINCIPAL FINDINGS: Our in-house bank of compounds was screened for inhibition of three PBPs from resistant bacteria: PBP2a from Methicillin-resistant Staphylococcus aureus (MRSA), PBP2x from Streptococcus pneumoniae strain 5204, and PBP5fm from Enterococcus faecium strain D63r. Initial hit inhibitor obtained by screening was then used as a starting point for computational similarity searching for structurally related compounds and several new noncovalent inhibitors were discovered. Two compounds had promising inhibitory activities of both PBP2a and PBP2x 5204, and good in-vitro antibacterial activities against a panel of Gram-positive bacterial strains. CONCLUSIONS: We found new noncovalent inhibitors of PBPs which represent important starting points for development of more potent inhibitors of PBPs that can target penicillin-resistant bacteria.
Centre de Recherches du Cyclotron - CRC ; Centre d'Ingénierie des Protéines - CIP
Union Européenne = European Union - UE = EU
Researchers ; Professionals

File(s) associated to this reference

Fulltext file(s):

Restricted access
Turk_2011.pdfPublisher postprint1.51 MBRequest copy

Bookmark and Share SFX Query

All documents in ORBi are protected by a user license.