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New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria
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 transpeptidat...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090393/ https://www.ncbi.nlm.nih.gov/pubmed/21573060 http://dx.doi.org/10.1371/journal.pone.0019418 |
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author | Turk, Samo Verlaine, Olivier Gerards, Thomas Živec, Matej Humljan, Jan Sosič, Izidor Amoroso, Ana Zervosen, Astrid Luxen, André Joris, Bernard Gobec, Stanislav |
author_facet | Turk, Samo Verlaine, Olivier Gerards, Thomas Živec, Matej Humljan, Jan Sosič, Izidor Amoroso, Ana Zervosen, Astrid Luxen, André Joris, Bernard Gobec, Stanislav |
author_sort | Turk, Samo |
collection | PubMed |
description | 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. 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. |
format | Text |
id | pubmed-3090393 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30903932011-05-13 New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria Turk, Samo Verlaine, Olivier Gerards, Thomas Živec, Matej Humljan, Jan Sosič, Izidor Amoroso, Ana Zervosen, Astrid Luxen, André Joris, Bernard Gobec, Stanislav PLoS One Research Article 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. 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. Public Library of Science 2011-05-09 /pmc/articles/PMC3090393/ /pubmed/21573060 http://dx.doi.org/10.1371/journal.pone.0019418 Text en Turk et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Turk, Samo Verlaine, Olivier Gerards, Thomas Živec, Matej Humljan, Jan Sosič, Izidor Amoroso, Ana Zervosen, Astrid Luxen, André Joris, Bernard Gobec, Stanislav New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria |
title | New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria |
title_full | New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria |
title_fullStr | New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria |
title_full_unstemmed | New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria |
title_short | New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria |
title_sort | new noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090393/ https://www.ncbi.nlm.nih.gov/pubmed/21573060 http://dx.doi.org/10.1371/journal.pone.0019418 |
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