Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria
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-negat...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/4/2062 |
| Summary: | 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 (<b>7</b>–<b>23</b>) were tested for oxacillin adjuvant properties in the Methicillin-susceptible <i>S. aureus</i> (MSSA) strain ATCC 25923 and Methicillin-resistant <i>S. aureus</i> MRSA 19449. Compounds <b>14</b>–<b>16</b> 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 <i>K. aerogenes</i> to determine the potential of compounds <b>7</b>–<b>23</b> to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (<b>10</b>, <b>15</b>) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while <b>15</b> 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% (<b>19</b>). The 4-phenylbenzylidene derivative (<b>15</b>) demonstrated significant MDR-reversal “dual action” for <i>β</i>-lactam antibiotics in MRSA and inhibited AcrAB-TolC in <i>K. aerogenes</i>. <b>15</b> displayed also satisfied solubility and safety towards CYP3A4 in vitro. |
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| ISSN: | 1661-6596 1422-0067 |