Comprehensive safety and toxicity analysis of 2,2’-Bipyridine derivatives in combating MRSA biofilm formation and persistence
IntroductionMethicillin-resistant Staphylococcus aureus (MRSA) infections have become arduous to treat due to their capacity to form biofilms, develop persistence, and exhibit significant antimicrobial resistance. These factors contribute to the complexity of managing MRSA infections and highlight t...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2025.1493679/full |
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| author | Priyanka Priyanka Mohini Sharma Bhavna Vaid Bhavna Vaid Ram Bharti Ram Bharti Sachin Raut Sachin Raut R. S. Jolly Neeraj Khatri Neeraj Khatri |
| author_facet | Priyanka Priyanka Mohini Sharma Bhavna Vaid Bhavna Vaid Ram Bharti Ram Bharti Sachin Raut Sachin Raut R. S. Jolly Neeraj Khatri Neeraj Khatri |
| author_sort | Priyanka |
| collection | DOAJ |
| description | IntroductionMethicillin-resistant Staphylococcus aureus (MRSA) infections have become arduous to treat due to their capacity to form biofilms, develop persistence, and exhibit significant antimicrobial resistance. These factors contribute to the complexity of managing MRSA infections and highlight the urgent need for innovative treatment strategies.ObjectivesThis endeavor aims to evaluate the safety of 2,2’-Bipyridine (2,2’-Bipy) derivatives and their antimicrobial, anti-biofilm, and anti-persister activities in treating MRSA Infections.MethodsSix derivatives were screened for their ADMET properties and tested for minimum inhibitory concentrations against various bacterial strains using agar well diffusion and broth dilution. Safety studies were conducted through hemolysis tests, cell viability assays, and in vivo acute oral toxicity examinations. Bactericidal mechanisms and biofilm disruption effects were analyzed using crystal violet staining and confocal microscopy assays. The murine thigh infection model was also used to investigate the in vivo efficacy.ResultsAll derivatives exhibited favorable physicochemical profiles and ADMET properties and are predicted to be safe based on their drug-like properties. in vitro studies demonstrated that derivatives are non-toxic to 3T3 L1, and in vivo studies confirmed their safety in mice at a dose of 300 mg/kg and their non-hemolytic nature against rabbit red blood cells. All compounds showed potent antibacterial activity against the tested bacteria, including the resistant MRSA strain 831. They inhibited biofilm formation and eradicated biofilms in a dose-dependent manner against MTCC 737 and MRSA 831, and they effectively eliminated MRSA persister cells, outperforming the reference antibiotic vancomycin. These derivatives were found to depolarize the mitochondrial membrane and accumulate intracellular reactive oxygen species. These derivatives significantly reduced the bacterial load in the murine thigh infection model.ConclusionThe study concluded that 2,2’-Bipy derivatives possess significant antimicrobial activity, are non-toxic, and are effective in inhibiting biofilm formation and killing persister cells. |
| format | Article |
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| institution | Kabale University |
| issn | 2235-2988 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj-art-6cff4deaeccd401ca08c6ade3d38c7512025-01-24T07:14:26ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882025-01-011510.3389/fcimb.2025.14936791493679Comprehensive safety and toxicity analysis of 2,2’-Bipyridine derivatives in combating MRSA biofilm formation and persistence Priyanka0 Priyanka1Mohini Sharma2Bhavna Vaid3Bhavna Vaid4Ram Bharti5Ram Bharti6Sachin Raut7Sachin Raut8R. S. Jolly9Neeraj Khatri10Neeraj Khatri11IMTECH Centre for Animal Resources & Experimentation (iCARE), Council of Scientific and Industrial Research (CSIR)-Institute of Microbial Technology, Chandigarh, IndiaAcademy of Scientific and Innovative Research, Ghaziabad, IndiaIMTECH Centre for Animal Resources & Experimentation (iCARE), Council of Scientific and Industrial Research (CSIR)-Institute of Microbial Technology, Chandigarh, IndiaIMTECH Centre for Animal Resources & Experimentation (iCARE), Council of Scientific and Industrial Research (CSIR)-Institute of Microbial Technology, Chandigarh, IndiaPG Department of Chemistry, Sri Guru Tegh Bahadur (SGTB) Khalsa College, Sri Anandpur Sahib, Punjab, IndiaIMTECH Centre for Animal Resources & Experimentation (iCARE), Council of Scientific and Industrial Research (CSIR)-Institute of Microbial Technology, Chandigarh, IndiaAcademy of Scientific and Innovative Research, Ghaziabad, IndiaIMTECH Centre for Animal Resources & Experimentation (iCARE), Council of Scientific and Industrial Research (CSIR)-Institute of Microbial Technology, Chandigarh, IndiaAcademy of Scientific and Innovative Research, Ghaziabad, IndiaCouncil of Scientific and Industrial Research (CSIR)-Institute of Microbial Technology, Chandigarh, IndiaIMTECH Centre for Animal Resources & Experimentation (iCARE), Council of Scientific and Industrial Research (CSIR)-Institute of Microbial Technology, Chandigarh, IndiaAcademy of Scientific and Innovative Research, Ghaziabad, IndiaIntroductionMethicillin-resistant Staphylococcus aureus (MRSA) infections have become arduous to treat due to their capacity to form biofilms, develop persistence, and exhibit significant antimicrobial resistance. These factors contribute to the complexity of managing MRSA infections and highlight the urgent need for innovative treatment strategies.ObjectivesThis endeavor aims to evaluate the safety of 2,2’-Bipyridine (2,2’-Bipy) derivatives and their antimicrobial, anti-biofilm, and anti-persister activities in treating MRSA Infections.MethodsSix derivatives were screened for their ADMET properties and tested for minimum inhibitory concentrations against various bacterial strains using agar well diffusion and broth dilution. Safety studies were conducted through hemolysis tests, cell viability assays, and in vivo acute oral toxicity examinations. Bactericidal mechanisms and biofilm disruption effects were analyzed using crystal violet staining and confocal microscopy assays. The murine thigh infection model was also used to investigate the in vivo efficacy.ResultsAll derivatives exhibited favorable physicochemical profiles and ADMET properties and are predicted to be safe based on their drug-like properties. in vitro studies demonstrated that derivatives are non-toxic to 3T3 L1, and in vivo studies confirmed their safety in mice at a dose of 300 mg/kg and their non-hemolytic nature against rabbit red blood cells. All compounds showed potent antibacterial activity against the tested bacteria, including the resistant MRSA strain 831. They inhibited biofilm formation and eradicated biofilms in a dose-dependent manner against MTCC 737 and MRSA 831, and they effectively eliminated MRSA persister cells, outperforming the reference antibiotic vancomycin. These derivatives were found to depolarize the mitochondrial membrane and accumulate intracellular reactive oxygen species. These derivatives significantly reduced the bacterial load in the murine thigh infection model.ConclusionThe study concluded that 2,2’-Bipy derivatives possess significant antimicrobial activity, are non-toxic, and are effective in inhibiting biofilm formation and killing persister cells.https://www.frontiersin.org/articles/10.3389/fcimb.2025.1493679/full2,2’-bipyridine derivativesMRSA biofilmscytotoxicityantibacterial activityacute oral toxicityADMET |
| spellingShingle | Priyanka Priyanka Mohini Sharma Bhavna Vaid Bhavna Vaid Ram Bharti Ram Bharti Sachin Raut Sachin Raut R. S. Jolly Neeraj Khatri Neeraj Khatri Comprehensive safety and toxicity analysis of 2,2’-Bipyridine derivatives in combating MRSA biofilm formation and persistence Frontiers in Cellular and Infection Microbiology 2,2’-bipyridine derivatives MRSA biofilms cytotoxicity antibacterial activity acute oral toxicity ADMET |
| title | Comprehensive safety and toxicity analysis of 2,2’-Bipyridine derivatives in combating MRSA biofilm formation and persistence |
| title_full | Comprehensive safety and toxicity analysis of 2,2’-Bipyridine derivatives in combating MRSA biofilm formation and persistence |
| title_fullStr | Comprehensive safety and toxicity analysis of 2,2’-Bipyridine derivatives in combating MRSA biofilm formation and persistence |
| title_full_unstemmed | Comprehensive safety and toxicity analysis of 2,2’-Bipyridine derivatives in combating MRSA biofilm formation and persistence |
| title_short | Comprehensive safety and toxicity analysis of 2,2’-Bipyridine derivatives in combating MRSA biofilm formation and persistence |
| title_sort | comprehensive safety and toxicity analysis of 2 2 bipyridine derivatives in combating mrsa biofilm formation and persistence |
| topic | 2,2’-bipyridine derivatives MRSA biofilms cytotoxicity antibacterial activity acute oral toxicity ADMET |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2025.1493679/full |
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