New noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria

• Published in: PloS one Vol. 6; no. 5; p. e19418
• Main Authors: Turk, Samo, Verlaine, Olivier, Gerards, Thomas, Zivec, Matej, Humljan, Jan, Sosič, Izidor, Amoroso, Ana, Zervosen, Astrid, Luxen, André, Joris, Bernard, Gobec, Stanislav
• Format: Journal Article Web Resource
• Language: English
• Published: United States Public Library of Science 09.05.2011; Public Library of Science (PLoS)
• Subjects: Acylation; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics; Bacteria; Bacterial infections; Banks (Finance); Binding; Binding proteins; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Biology; Biosynthesis; Chemistry; Computer applications; Coordination compounds; Cross infection; Drug resistance; Drug Resistance, Bacterial - drug effects; Enterococcus faecium - drug effects; Enterococcus faecium - metabolism; Enzymes; Gram-Positive Bacteria - drug effects; Gram-Positive Bacteria - metabolism; Infectious diseases; Inhibitors; Laboratories; Lactams; Life sciences; Medicine; Methicillin; Microbial drug resistance; Microbial Sensitivity Tests; Molecular Structure; Mutation; Organic chemistry; Penicillin; Penicillin-Binding Proteins - antagonists & inhibitors; Penicillins - pharmacology; Peptide Synthases - antagonists & inhibitors; Pharmacy; Pneumonia; Protein binding; Proteins; Queries; Sciences du vivant; Search engines; Staphylococcus aureus; Staphylococcus infections; Streptococcus infections; Streptococcus pneumoniae; Streptococcus pneumoniae - drug effects; Streptococcus pneumoniae - metabolism; Slovenia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0019418

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. 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. 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.