High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coli
Abstract The DfrA1 protein provides trimethoprim resistance in bacteria, especially Klebsiella pneumoniae and Escherichia coli, by modifying dihydrofolate reductase, which reduces the binding efficacy of the antibiotic. This study identified inhibitors of the trimethoprim-resistant DfrA1 protein thr...
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s41598-025-91410-4 |
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| author | Soharth Hasnat Soaibur Rahman Meherun Binta Alam Farha Mohi Suin Farzana Yeasmin Tanjila Suha Nahuna Tanjin Supty Sal Sabila Animesh Chowdhury A. D. A. Shahinuzzaman M. Murshida Mahbub Tofazzal Islam M. Nazmul Hoque |
| author_facet | Soharth Hasnat Soaibur Rahman Meherun Binta Alam Farha Mohi Suin Farzana Yeasmin Tanjila Suha Nahuna Tanjin Supty Sal Sabila Animesh Chowdhury A. D. A. Shahinuzzaman M. Murshida Mahbub Tofazzal Islam M. Nazmul Hoque |
| author_sort | Soharth Hasnat |
| collection | DOAJ |
| description | Abstract The DfrA1 protein provides trimethoprim resistance in bacteria, especially Klebsiella pneumoniae and Escherichia coli, by modifying dihydrofolate reductase, which reduces the binding efficacy of the antibiotic. This study identified inhibitors of the trimethoprim-resistant DfrA1 protein through high-throughput computational screening and optimization of 3,601 newly synthesized chemical compounds from the ChemDiv database, aiming to discover potential drug candidates targeting DfrA1 in K. pneumoniae and E. coli. Through this approach, we identified six promising DCs, labeled DC1 to DC6, as potential inhibitors of DfrA1. Each DC showed a strong ability to bind effectively to the DfrA1 protein and formed favorable chemical interactions at the binding sites. These interactions were comparable to those of Iclaprim, a well-known antibiotic effective against DfrA1. To confirm our findings, we explored how the promising DCs work at the molecular level, focusing on their thermodynamic properties. Additionally, molecular dynamics simulations confirmed the ability of these six DCs to effectively inhibit the DfrA1 protein. Our results showed that DC4 (an organofluorinated compound) and DC6 (a benzimidazole compound) exhibited potential efficacy against the DfrA1 protein than the control drug, particularly regarding stability, solvent-accessible surface area, solvent exposure, polarity, and binding site interactions, which influence their residence time and efficacy. Overall, findings of this study suggest that DC4 and DC6 have the potential to act as inhibitors against the DfrA1, offering promising prospects for the treatment and management of infections caused by trimethoprim-resistant K. pneumoniae and E. coli in both humans and animals. However, further in vitro validations are necessary. |
| format | Article |
| id | doaj-art-9e5e986c995241efb97cce0ad03f2ea8 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-9e5e986c995241efb97cce0ad03f2ea82025-08-20T03:04:01ZengNature PortfolioScientific Reports2045-23222025-02-0115111610.1038/s41598-025-91410-4High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coliSoharth Hasnat0Soaibur Rahman1Meherun Binta Alam2Farha Mohi Suin3Farzana Yeasmin4Tanjila Suha5Nahuna Tanjin Supty6Sal Sabila7Animesh Chowdhury8A. D. A. Shahinuzzaman9M. Murshida Mahbub10Tofazzal Islam11M. Nazmul Hoque12Department of Genetic Engineering and Biotechnology, East West UniversityDepartment of Genetic Engineering and Biotechnology, East West UniversityDepartment of Genetic Engineering and Biotechnology, East West UniversityDepartment of Genetic Engineering and Biotechnology, East West UniversityInstitute of Biotechnology and Genetic Engineering, Gazipur Agricultural University (GAU)Department of Genetic Engineering and Biotechnology, East West UniversityDepartment of Genetic Engineering and Biotechnology, East West UniversityDepartment of Genetic Engineering and Biotechnology, East West UniversityDepartment of Genetic Engineering and Biotechnology, East West UniversityPharmaceutical Sciences Research Division, Bangladesh Council of Scientific and Industrial Research (BCSIR)Department of Genetic Engineering and Biotechnology, East West UniversityInstitute of Biotechnology and Genetic Engineering, Gazipur Agricultural University (GAU)Molecular Biology and Bioinformatics Laboratory, Department of Gynecology, Obstetrics and Reproductive Health, Gazipur Agricultural University (GAU)Abstract The DfrA1 protein provides trimethoprim resistance in bacteria, especially Klebsiella pneumoniae and Escherichia coli, by modifying dihydrofolate reductase, which reduces the binding efficacy of the antibiotic. This study identified inhibitors of the trimethoprim-resistant DfrA1 protein through high-throughput computational screening and optimization of 3,601 newly synthesized chemical compounds from the ChemDiv database, aiming to discover potential drug candidates targeting DfrA1 in K. pneumoniae and E. coli. Through this approach, we identified six promising DCs, labeled DC1 to DC6, as potential inhibitors of DfrA1. Each DC showed a strong ability to bind effectively to the DfrA1 protein and formed favorable chemical interactions at the binding sites. These interactions were comparable to those of Iclaprim, a well-known antibiotic effective against DfrA1. To confirm our findings, we explored how the promising DCs work at the molecular level, focusing on their thermodynamic properties. Additionally, molecular dynamics simulations confirmed the ability of these six DCs to effectively inhibit the DfrA1 protein. Our results showed that DC4 (an organofluorinated compound) and DC6 (a benzimidazole compound) exhibited potential efficacy against the DfrA1 protein than the control drug, particularly regarding stability, solvent-accessible surface area, solvent exposure, polarity, and binding site interactions, which influence their residence time and efficacy. Overall, findings of this study suggest that DC4 and DC6 have the potential to act as inhibitors against the DfrA1, offering promising prospects for the treatment and management of infections caused by trimethoprim-resistant K. pneumoniae and E. coli in both humans and animals. However, further in vitro validations are necessary.https://doi.org/10.1038/s41598-025-91410-4TrimethoprimAntimicrobial resistanceDfrA1InhibitorsHigh-throughput screeningComputational drug discovery |
| spellingShingle | Soharth Hasnat Soaibur Rahman Meherun Binta Alam Farha Mohi Suin Farzana Yeasmin Tanjila Suha Nahuna Tanjin Supty Sal Sabila Animesh Chowdhury A. D. A. Shahinuzzaman M. Murshida Mahbub Tofazzal Islam M. Nazmul Hoque High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coli Scientific Reports Trimethoprim Antimicrobial resistance DfrA1 Inhibitors High-throughput screening Computational drug discovery |
| title | High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coli |
| title_full | High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coli |
| title_fullStr | High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coli |
| title_full_unstemmed | High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coli |
| title_short | High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coli |
| title_sort | high throughput screening identifies potential inhibitors targeting trimethoprim resistant dfra1 protein in klebsiella pneumoniae and escherichia coli |
| topic | Trimethoprim Antimicrobial resistance DfrA1 Inhibitors High-throughput screening Computational drug discovery |
| url | https://doi.org/10.1038/s41598-025-91410-4 |
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