title: New noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria.
abstract: BACKGROUND
  Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs β-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 β-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs.
  
  
  RESULTS
  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.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Olivier
authors.initials: O
authors.lastname: Verlaine
authors.forename: Thomas
authors.initials: T
authors.lastname: Gerards
authors.forename: Matej
authors.initials: M
authors.lastname: Zivec
authors.forename: Jan
authors.initials: J
authors.lastname: Humljan
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.forename: Ana
authors.initials: A
authors.lastname: Amoroso
authors.forename: Astrid
authors.initials: A
authors.lastname: Zervosen
authors.forename: André
authors.initials: A
authors.lastname: Luxen
authors.forename: Bernard
authors.initials: B
authors.lastname: Joris
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D016984:Enterococcus faecium / Q000187:drug effects / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors*; D010406:Penicillins / Q000494:pharmacology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D046915:Penicillin-Binding Proteins; D010406:Penicillins; C478699:penicillin-binding protein 2a, Streptococcus; C072223:PBP 2x protein, Streptococcus; D010453:Peptide Synthases