Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria

• Published in: International journal of molecular sciences 2021-02, Vol.22 (4), p.2062
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 5-arylideneimidazolones; Allosteric Site; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibiotic adjuvant; Bacteria - drug effects; Crystallography, X-Ray; Drug Evaluation, Preclinical; Drug Interactions; Drug Resistance, Multiple, Bacterial - drug effects; Drug Resistance, Multiple, Bacterial - genetics; Hydrogen Bonding; Hydrogen-Ion Concentration; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Klebsiella aerogenes; Ligands; Microbial Sensitivity Tests; Molecular Conformation; Molecular Docking Simulation; Morpholines - chemical synthesis; Morpholines - chemistry; Morpholines - pharmacology; MRSA; multidrug resistance; Solubility; Staphylococcus aureus; Structure-Activity Relationship; Water
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22042062

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 ( - ) were tested for oxacillin adjuvant properties in the Methicillin-susceptible (MSSA) strain ATCC 25923 and Methicillin-resistant MRSA 19449. Compounds - 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 to determine the potential of compounds - to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds ( , ) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 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% ( ). The 4-phenylbenzylidene derivative ( ) demonstrated significant MDR-reversal "dual action" for -lactam antibiotics in MRSA and inhibited AcrAB-TolC in . displayed also satisfied solubility and safety towards CYP3A4 in vitro.