Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A

Publication type:
Journal article
Metadata:
Autoren
  • Fabian Barthels
  • Gabriella Marincola
  • Tessa Marciniak
  • Matthias Konhaeuser
  • Stefan Hammerschmidt
  • Jan Bierlmeier
  • Ute Distler
  • Peter R Wich
  • Stefan Tenzer
  • Dirk Schwarzer
  • Wilma Ziebuhr
  • Tanja Schirmeister
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000521388500001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1002/cmdc.201900687
eISSN
1860-7187
Externe Identifier
  • Clarivate Analytics Document Solution ID: LP3JV
  • PubMed Identifier: 32118357
ISSN
1860-7179
Ausgabe der Veröffentlichung
10
Zeitschrift
CHEMMEDCHEM
Schlüsselwörter
  • Antibiotics
  • biofilm
  • drug design
  • sortase A
  • Staphylococcus aureus
Paginierung
839 - 850
Datum der Veröffentlichung
2020
Status
Published
Titel
Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of <i>Staphylococcus aureus</i> Sortase A
Sub types
  • Article
Ausgabe der Zeitschrift
15

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:title>Abstract</jats:title><jats:p><jats:italic>Staphylococcus aureus</jats:italic> is one of the most frequent causes of nosocomial and community‐acquired infections, with drug‐resistant strains being responsible for tens of thousands of deaths per year. <jats:italic>S. aureus</jats:italic> sortase A inhibitors are designed to interfere with virulence determinants. We have identified disulfanylbenzamides as a new class of potent inhibitors against sortase A that act by covalent modification of the active‐site cysteine. A broad series of derivatives were synthesized to derive structure‐activity relationships (SAR). <jats:italic>In vitro</jats:italic> and <jats:italic>in silico</jats:italic> methods allowed the experimentally observed binding affinities and selectivities to be rationalized. The most active compounds were found to have single‐digit micromolar <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values and caused up to a 66 % reduction of <jats:italic>S. aureus</jats:italic> fibrinogen attachment at an effective inhibitor concentration of 10 μM. This new molecule class exhibited minimal cytotoxicity, low bacterial growth inhibition and impaired sortase‐mediated adherence of <jats:italic>S. aureus</jats:italic> cells.</jats:p>
Autoren
  • Fabian Barthels
  • Gabriella Marincola
  • Tessa Marciniak
  • Matthias Konhäuser
  • Stefan Hammerschmidt
  • Jan Bierlmeier
  • Ute Distler
  • Peter R Wich
  • Stefan Tenzer
  • Dirk Schwarzer
  • Wilma Ziebuhr
  • Tanja Schirmeister
DOI
10.1002/cmdc.201900687
eISSN
1860-7187
ISSN
1860-7179
Ausgabe der Veröffentlichung
10
Zeitschrift
ChemMedChem
Sprache
en
Online publication date
2020
Paginierung
839 - 850
Datum der Veröffentlichung
2020
Status
Published
Herausgeber
Wiley
Herausgeber URL
http://dx.doi.org/10.1002/cmdc.201900687
Datum der Datenerfassung
2023
Titel
Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of <i>Staphylococcus aureus</i> Sortase A
Ausgabe der Zeitschrift
15

Data source: Crossref

Abstract
Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with drug-resistant strains being responsible for tens of thousands of deaths per year. S. aureus sortase A inhibitors are designed to interfere with virulence determinants. We have identified disulfanylbenzamides as a new class of potent inhibitors against sortase A that act by covalent modification of the active-site cysteine. A broad series of derivatives were synthesized to derive structure-activity relationships (SAR). In vitro and in silico methods allowed the experimentally observed binding affinities and selectivities to be rationalized. The most active compounds were found to have single-digit micromolar K<sub>i</sub> values and caused up to a 66 % reduction of S. aureus fibrinogen attachment at an effective inhibitor concentration of 10 μM. This new molecule class exhibited minimal cytotoxicity, low bacterial growth inhibition and impaired sortase-mediated adherence of S. aureus cells.
Addresses
  • Institute for Pharmacy and Biochemistry, Johannes-Gutenberg-University of Mainz, Staudinger Weg 5, 55128, Mainz, Germany.
Autoren
  • Fabian Barthels
  • Gabriella Marincola
  • Tessa Marciniak
  • Matthias Konhäuser
  • Stefan Hammerschmidt
  • Jan Bierlmeier
  • Ute Distler
  • Peter R Wich
  • Stefan Tenzer
  • Dirk Schwarzer
  • Wilma Ziebuhr
  • Tanja Schirmeister
DOI
10.1002/cmdc.201900687
eISSN
1860-7187
Externe Identifier
  • PubMed Identifier: 32118357
  • PubMed Central ID: PMC7318353
Open access
true
ISSN
1860-7179
Ausgabe der Veröffentlichung
10
Zeitschrift
ChemMedChem
Schlüsselwörter
  • Staphylococcus aureus
  • Benzamides
  • Cysteine Endopeptidases
  • Aminoacyltransferases
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Anti-Bacterial Agents
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship
  • Dose-Response Relationship, Drug
Sprache
eng
Medium
Print-Electronic
Online publication date
2020
Open access status
Open Access
Paginierung
839 - 850
Datum der Veröffentlichung
2020
Status
Published
Publisher licence
CC BY-NC-ND
Datum der Datenerfassung
2020
Titel
Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
15

Files

https://europepmc.org/articles/PMC7318353?pdf=render

Data source: Europe PubMed Central

Abstract
Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with drug-resistant strains being responsible for tens of thousands of deaths per year. S. aureus sortase A inhibitors are designed to interfere with virulence determinants. We have identified disulfanylbenzamides as a new class of potent inhibitors against sortase A that act by covalent modification of the active-site cysteine. A broad series of derivatives were synthesized to derive structure-activity relationships (SAR). In vitro and in silico methods allowed the experimentally observed binding affinities and selectivities to be rationalized. The most active compounds were found to have single-digit micromolar Ki values and caused up to a 66 % reduction of S. aureus fibrinogen attachment at an effective inhibitor concentration of 10 μM. This new molecule class exhibited minimal cytotoxicity, low bacterial growth inhibition and impaired sortase-mediated adherence of S. aureus cells.
Autoren
  • Fabian Barthels
  • Gabriella Marincola
  • Tessa Marciniak
  • Matthias Konhäuser
  • Stefan Hammerschmidt
  • Jan Bierlmeier
  • Ute Distler
  • Peter R Wich
  • Stefan Tenzer
  • Dirk Schwarzer
  • Wilma Ziebuhr
  • Tanja Schirmeister
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/32118357
DOI
10.1002/cmdc.201900687
eISSN
1860-7187
Externe Identifier
  • PubMed Central ID: PMC7318353
Ausgabe der Veröffentlichung
10
Zeitschrift
ChemMedChem
Schlüsselwörter
  • Antibiotics
  • Staphylococcus aureus
  • biofilm
  • drug design
  • sortase A
  • Aminoacyltransferases
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Benzamides
  • Cysteine Endopeptidases
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Staphylococcus aureus
  • Structure-Activity Relationship
Sprache
eng
Country
Germany
Paginierung
839 - 850
Datum der Veröffentlichung
2020
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
15

Data source: PubMed

Author's licence
CC-BY-NC-ND
Autoren
  • Fabian Barthels
  • Gabriella Marincola
  • Tessa Marciniak
  • Matthias Konhäuser
  • Stefan Hammerschmidt
  • Jan Bierlmeier
  • Ute Distler
  • Peter R Wich
  • Stefan Tenzer
  • Dirk Schwarzer
  • Wilma Ziebuhr
  • Tanja Schirmeister
Hosting institution
Universitätsbibliothek Mainz
Sammlungen
  • JGU-Publikationen
Resource version
Published version
DOI
10.1002/cmdc.201900687
File(s) embargoed
false
Open access
true
ISSN
1860-7187
Ausgabe der Veröffentlichung
10
Zeitschrift
ChemMedChem
Schlüsselwörter
  • 570 Biowissenschaften
  • 570 Life sciences
Sprache
eng
Open access status
Open Access
Paginierung
839 - 850
Datum der Veröffentlichung
2020
Public URL
https://openscience.ub.uni-mainz.de/handle/20.500.12030/6271
Herausgeber
Wiley-VCH
Herausgeber URL
https://doi.org/10.1002/cmdc.201900687
Datum der Datenerfassung
2021
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Zugang
Public
Titel
Asymmetric disulfanylbenzamides as irreversible and selective inhibitors of Staphylococcus aureus sortase A
Ausgabe der Zeitschrift
15

Files

barthels_fabian-asymmetric_dis-20210805114859449.pdf

Data source: OPENSCIENCE.UB

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