Efflux Pump-Binding 4(3-Aminocyclobutyl)Pyrimidin-2-Amines Are Colloidal Aggregators
Efflux pumps are a relevant factor in antimicrobial resistance. In <i>E. coli</i>, the tripartite efflux pump AcrAB-TolC removes a chemically diverse set of antibiotics from the bacterium. Therefore, small molecules interfering with efflux pump function are considered adjuvants for impro...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/6/1000 |
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| author | Tania Szal Shweta Singh Chauhan Philipp Lewe Fatima-Zahra Rachad Marina Madre Laura Paunina Susanne Witt Ramakrishnan Parthasarathi Björn Windshügel |
| author_facet | Tania Szal Shweta Singh Chauhan Philipp Lewe Fatima-Zahra Rachad Marina Madre Laura Paunina Susanne Witt Ramakrishnan Parthasarathi Björn Windshügel |
| author_sort | Tania Szal |
| collection | DOAJ |
| description | Efflux pumps are a relevant factor in antimicrobial resistance. In <i>E. coli</i>, the tripartite efflux pump AcrAB-TolC removes a chemically diverse set of antibiotics from the bacterium. Therefore, small molecules interfering with efflux pump function are considered adjuvants for improving antimicrobial therapies. Several compounds targeting the periplasmic adapter protein AcrA and the efflux pump AcrB have been identified to act synergistically with different antibiotics. Among those, several 4(3-aminocyclobutyl)pyrimidin-2-amines have been shown to bind to both proteins. In this study, we intended to identify analogs of these substances with improved binding affinity to AcrA using virtual screening followed by experimental validation. While we succeeded in identifying several compounds showing a synergistic effect with erythromycin on <i>E. coli</i>, biophysical studies suggested that 4(3-aminocyclobutyl)pyrimidin-2-amines form colloidal aggregates that do not bind specifically to AcrA. Therefore, these substances are not suited for further development. Our study emphasizes the importance of implementing additional control experiments to identify aggregators among bioactive compounds. |
| first_indexed | 2024-03-11T02:42:05Z |
| format | Article |
| id | doaj.art-b61ee0133e1e4f9d85b6ebd6a4171f79 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T02:42:05Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-b61ee0133e1e4f9d85b6ebd6a4171f792023-11-18T09:31:45ZengMDPI AGBiomolecules2218-273X2023-06-01136100010.3390/biom13061000Efflux Pump-Binding 4(3-Aminocyclobutyl)Pyrimidin-2-Amines Are Colloidal AggregatorsTania Szal0Shweta Singh Chauhan1Philipp Lewe2Fatima-Zahra Rachad3Marina Madre4Laura Paunina5Susanne Witt6Ramakrishnan Parthasarathi7Björn Windshügel8Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, GermanyComputational Toxicology Facility, Toxicoinformatics & Industrial Research CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, IndiaCentre for Structural Systems Biology (CSSB), University Medical Center Hamburg-Eppendorf (UKE), 22607 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, GermanyLatvian Institute of Organic Synthesis, LV-1006 Riga, LatviaLatvian Institute of Organic Synthesis, LV-1006 Riga, LatviaCentre for Structural Systems Biology (CSSB), University Medical Center Hamburg-Eppendorf (UKE), 22607 Hamburg, GermanyComputational Toxicology Facility, Toxicoinformatics & Industrial Research CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, IndiaFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, GermanyEfflux pumps are a relevant factor in antimicrobial resistance. In <i>E. coli</i>, the tripartite efflux pump AcrAB-TolC removes a chemically diverse set of antibiotics from the bacterium. Therefore, small molecules interfering with efflux pump function are considered adjuvants for improving antimicrobial therapies. Several compounds targeting the periplasmic adapter protein AcrA and the efflux pump AcrB have been identified to act synergistically with different antibiotics. Among those, several 4(3-aminocyclobutyl)pyrimidin-2-amines have been shown to bind to both proteins. In this study, we intended to identify analogs of these substances with improved binding affinity to AcrA using virtual screening followed by experimental validation. While we succeeded in identifying several compounds showing a synergistic effect with erythromycin on <i>E. coli</i>, biophysical studies suggested that 4(3-aminocyclobutyl)pyrimidin-2-amines form colloidal aggregates that do not bind specifically to AcrA. Therefore, these substances are not suited for further development. Our study emphasizes the importance of implementing additional control experiments to identify aggregators among bioactive compounds.https://www.mdpi.com/2218-273X/13/6/1000efflux pumpsAcrAefflux pump inhibitor<i>E. coli</i>virtual screeningantimicrobial studies |
| spellingShingle | Tania Szal Shweta Singh Chauhan Philipp Lewe Fatima-Zahra Rachad Marina Madre Laura Paunina Susanne Witt Ramakrishnan Parthasarathi Björn Windshügel Efflux Pump-Binding 4(3-Aminocyclobutyl)Pyrimidin-2-Amines Are Colloidal Aggregators Biomolecules efflux pumps AcrA efflux pump inhibitor <i>E. coli</i> virtual screening antimicrobial studies |
| title | Efflux Pump-Binding 4(3-Aminocyclobutyl)Pyrimidin-2-Amines Are Colloidal Aggregators |
| title_full | Efflux Pump-Binding 4(3-Aminocyclobutyl)Pyrimidin-2-Amines Are Colloidal Aggregators |
| title_fullStr | Efflux Pump-Binding 4(3-Aminocyclobutyl)Pyrimidin-2-Amines Are Colloidal Aggregators |
| title_full_unstemmed | Efflux Pump-Binding 4(3-Aminocyclobutyl)Pyrimidin-2-Amines Are Colloidal Aggregators |
| title_short | Efflux Pump-Binding 4(3-Aminocyclobutyl)Pyrimidin-2-Amines Are Colloidal Aggregators |
| title_sort | efflux pump binding 4 3 aminocyclobutyl pyrimidin 2 amines are colloidal aggregators |
| topic | efflux pumps AcrA efflux pump inhibitor <i>E. coli</i> virtual screening antimicrobial studies |
| url | https://www.mdpi.com/2218-273X/13/6/1000 |
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