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: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-02-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/4/2062 |
| _version_ | 1797396007838810112 |
|---|---|
| author | Aneta Kaczor Karolina Witek Sabina Podlewska Veronique Sinou Joanna Czekajewska Ewa Żesławska Agata Doroz-Płonka Annamaria Lubelska Gniewomir Latacz Wojciech Nitek Markus Bischoff Sandrine Alibert Jean-Marie Pagès Claus Jacob Elżbieta Karczewska Jean-Michel Bolla Jadwiga Handzlik |
| author_facet | Aneta Kaczor Karolina Witek Sabina Podlewska Veronique Sinou Joanna Czekajewska Ewa Żesławska Agata Doroz-Płonka Annamaria Lubelska Gniewomir Latacz Wojciech Nitek Markus Bischoff Sandrine Alibert Jean-Marie Pagès Claus Jacob Elżbieta Karczewska Jean-Michel Bolla Jadwiga Handzlik |
| author_sort | Aneta Kaczor |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T00:44:04Z |
| format | Article |
| id | doaj.art-c2c6b034475c4ff192bf10b33053ecf7 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:44:04Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c2c6b034475c4ff192bf10b33053ecf72023-12-11T17:40:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01224206210.3390/ijms22042062Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR BacteriaAneta Kaczor0Karolina Witek1Sabina Podlewska2Veronique Sinou3Joanna Czekajewska4Ewa Żesławska5Agata Doroz-Płonka6Annamaria Lubelska7Gniewomir Latacz8Wojciech Nitek9Markus Bischoff10Sandrine Alibert11Jean-Marie Pagès12Claus Jacob13Elżbieta Karczewska14Jean-Michel Bolla15Jadwiga Handzlik16Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, PolandDepartment of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, PolandDepartment of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, PolandUMR_MD1, U-1261, Aix Marseille Univ, INSERM, SSA, MCT, Faculté de Pharmacie, 27 Bd Jean Moulin, 13005 Marseille, FranceDepartment of Pharmaceutical Microbiology, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, PolandPedagogical University of Cracow, Institute of Biology, ul. Podchorążych 2, 30-084 Krakow, PolandDepartment of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, PolandDepartment of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, PolandDepartment of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, PolandFaculty of Chemistry, Jagiellonian University, ul. Gronostajowa 2, 30-387 Krakow, PolandInstitute for Medical Microbiology and Hygiene, Saarland University, D-66421 Homburg/Saar, GermanyUMR_MD1, U-1261, Aix Marseille Univ, INSERM, SSA, MCT, Faculté de Pharmacie, 27 Bd Jean Moulin, 13005 Marseille, FranceUMR_MD1, U-1261, Aix Marseille Univ, INSERM, SSA, MCT, Faculté de Pharmacie, 27 Bd Jean Moulin, 13005 Marseille, FranceDivision of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, GermanyDepartment of Pharmaceutical Microbiology, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, PolandUMR_MD1, U-1261, Aix Marseille Univ, INSERM, SSA, MCT, Faculté de Pharmacie, 27 Bd Jean Moulin, 13005 Marseille, FranceDepartment of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, PolandIn 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.https://www.mdpi.com/1422-0067/22/4/20625-arylideneimidazolonesmultidrug resistanceantibiotic adjuvant<i>Staphylococcus</i> <i>aureus</i>MRSA<i>Klebsiella aerogenes</i> |
| spellingShingle | Aneta Kaczor Karolina Witek Sabina Podlewska Veronique Sinou Joanna Czekajewska Ewa Żesławska Agata Doroz-Płonka Annamaria Lubelska Gniewomir Latacz Wojciech Nitek Markus Bischoff Sandrine Alibert Jean-Marie Pagès Claus Jacob Elżbieta Karczewska Jean-Michel Bolla Jadwiga Handzlik Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria International Journal of Molecular Sciences 5-arylideneimidazolones multidrug resistance antibiotic adjuvant <i>Staphylococcus</i> <i>aureus</i> MRSA <i>Klebsiella aerogenes</i> |
| title | Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria |
| title_full | Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria |
| title_fullStr | Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria |
| title_full_unstemmed | Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria |
| title_short | Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria |
| title_sort | molecular insights into an antibiotic enhancer action of new morpholine containing 5 arylideneimidazolones in the fight against mdr bacteria |
| topic | 5-arylideneimidazolones multidrug resistance antibiotic adjuvant <i>Staphylococcus</i> <i>aureus</i> MRSA <i>Klebsiella aerogenes</i> |
| url | https://www.mdpi.com/1422-0067/22/4/2062 |
| work_keys_str_mv | AT anetakaczor molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT karolinawitek molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT sabinapodlewska molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT veroniquesinou molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT joannaczekajewska molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT ewazesławska molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT agatadorozpłonka molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT annamarialubelska molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT gniewomirlatacz molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT wojciechnitek molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT markusbischoff molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT sandrinealibert molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT jeanmariepages molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT clausjacob molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT elzbietakarczewska molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT jeanmichelbolla molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria AT jadwigahandzlik molecularinsightsintoanantibioticenhanceractionofnewmorpholinecontaining5arylideneimidazolonesinthefightagainstmdrbacteria |