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 MRSA Klebsiella aerogenes PBP2a AcrAB-TolC 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 hdl:20.500.11880/30773 http://dx.doi.org/10.22028/D291-33456 |
ISSN: | 1422-0067 |
Date of registration: | 1-Mar-2021 |
Description of the related object: | Supplementary Materials |
Related object: | https://www.mdpi.com/1422-0067/22/4/2062/s1 |
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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ijms-22-02062.pdf | 6,07 MB | Adobe PDF | View/Open |
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