Article (Scientific journals)
New noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria.
Turk, Samo; Verlaine, Olivier; Gerards, Thomas et al.
2011In PLoS ONE, 6 (5), p. 19418
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Abstract :
[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.
Research center :
GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège
CIP - Centre d'Ingénierie des Protéines - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Turk, Samo
Verlaine, Olivier ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Gerards, Thomas ;  Université de Liège - ULiège > Labo de Bioénergétique
Zivec, Matej
Humljan, Jan
Sosic, Izidor
Amoroso, Ana Maria ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Zervosen, Astrid ;  Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse
Luxen, André ;  Université de Liège - ULiège > Département des sciences de la vie > Physiologie et génétique bactériennes
Joris, Bernard 
Gobec, Stanislav
Language :
English
Title :
New noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria.
Publication date :
2011
Journal title :
PLoS ONE
eISSN :
1932-6203
Publisher :
Public Library of Science, United States - California
Volume :
6
Issue :
5
Pages :
e19418
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
Eur-Intafar
Funders :
UE - Union Européenne [BE]
Available on ORBi :
since 01 September 2011

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