Please use this identifier to cite or link to this item: doi:10.22028/D291-33456
Title: Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria
Author(s): Kaczor, Aneta
Witek, Karolina
Podlewska, Sabina
Sinou, Veronique
Czekajewska, Joanna
Żesławska, Ewa
Doroz-Płonka, Agata
Lubelska, Annamaria
Latacz, Gniewomir
Nitek, Wojciech
Bischoff, Markus
Alibert, Sandrine
Pagès, Jean-Marie
Jacob, Claus
Karczewska, Elżbieta
Bolla, Jean-Michel
Handzlik, Jadwiga
Language: English
Title: International Journal of Molecular Sciences
Volume: 22
Issue: 4
Publisher/Platform: MDPI
Year of Publication: 2021
Free key words: 5-arylideneimidazolones
multidrug resistance
antibiotic adjuvant
Staphylococcus aureus
Klebsiella aerogenes
molecular docking
RTE assay
DDC notations: 500 Science
610 Medicine and health
Publikation type: Journal Article
Abstract: In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (7–23) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14–16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7–23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal “dual action” for β-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro.
DOI of the first publication: 10.3390/ijms22042062
Link to this record: urn:nbn:de:bsz:291--ds-334563
ISSN: 1422-0067
Date of registration: 1-Mar-2021
Description of the related object: Supplementary Materials
Related object:
Faculty: M - Medizinische Fakultät
NT - Naturwissenschaftlich- Technische Fakultät
Department: M - Infektionsmedizin
NT - Pharmazie
Professorship: M - Prof. Dr. Dr. Sören Becker
NT - Prof. Dr. Claus Jacob
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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