Please use this identifier to cite or link to this item: doi:10.22028/D291-35329
Title: N-Aryl mercaptoacetamides as potential multi-target inhibitors of metallo-β-lactamases (MBLs) and the virulence factor LasB from Pseudomonas aeruginosa
Author(s): Yahiaoui, Samir
Voos, Katrin
Haupenthal, Jörg
Wichelhaus, Thomas A.
Frank, Denia
Weizel, Lilia
Rotter, Marco
Brunst, Steffen
Kramer, Jan S.
Proschak, Ewgenij
Ducho, Christian
Hirsch, Anna K. H.
Language: English
Title: RSC Medicinal Chemistry
Volume: 12
Issue: 10
Pages: 1698–1708
Publisher/Platform: The Royal Society of Chemistry
Year of Publication: 2021
DDC notations: 500 Science
Publikation type: Journal Article
Abstract: Increasing antimicrobial resistance is evolving to be one of the major threats to public health. To reduce the selection pressure and thus to avoid a fast development of resistance, novel approaches aim to target bacterial virulence instead of growth. Another strategy is to restore the activity of antibiotics already in clinical use. This can be achieved by the inhibition of resistance factors such as metallo-β-lactamases (MBLs). Since MBLs can cleave almost all β-lactam antibiotics, including the “last resort” carbapenems, their inhibition is of utmost importance. Here, we report on the synthesis and in vitro evaluation of N-aryl mercaptoacetamides as inhibitors of both clinically relevant MBLs and the virulence factor LasB from Pseudomonas aeruginosa. All tested N-aryl mercaptoacetamides showed low micromolar to submicromolar activities on the tested enzymes IMP-7, NDM-1 and VIM-1. The two most promising compounds were further examined in NDM-1 expressing Klebsiella pneumoniae isolates, where they restored the full activity of imipenem. Together with their LasB-inhibitory activity in the micromolar range, this class of compounds can now serve as a starting point for a multi-target inhibitor approach against both bacterial resistance and virulence, which is unprecedented in antibacterial drug discovery.
DOI of the first publication: 10.1039/d1md00187f
URL of the first publication: https://pubs.rsc.org/en/content/articlelanding/2021/md/d1md00187f
Link to this record: urn:nbn:de:bsz:291--ds-353290
hdl:20.500.11880/32233
http://dx.doi.org/10.22028/D291-35329
ISSN: 2632-8682
Date of registration: 25-Jan-2022
Description of the related object: Supporting Information
Related object: https://www.rsc.org/suppdata/d1/md/d1md00187f/d1md00187f1.pdf
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Pharmazie
Professorship: NT - Prof. Dr. Christian Ducho
NT - Prof. Dr. Anna Hirsch
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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