Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI
Abstract Staphylococcus aureus infections have emerged as a global public health threat. Two key factors—drug resistance and biofilm formation—substantially impair the efficacy of the antimicrobial treatment for S. aureus infections using conventional antibiotics. Consequently, discovering novel ant...
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BMC
2025-07-01
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| Series: | BMC Microbiology |
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| Online Access: | https://doi.org/10.1186/s12866-025-04104-2 |
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| author | Yuanyuan Tang Han Deng Zhichao Xu Zhijian Yu Yong Xiang Zewen Wen Shiqing Han Zhong Chen Tieying Hou |
| author_facet | Yuanyuan Tang Han Deng Zhichao Xu Zhijian Yu Yong Xiang Zewen Wen Shiqing Han Zhong Chen Tieying Hou |
| author_sort | Yuanyuan Tang |
| collection | DOAJ |
| description | Abstract Staphylococcus aureus infections have emerged as a global public health threat. Two key factors—drug resistance and biofilm formation—substantially impair the efficacy of the antimicrobial treatment for S. aureus infections using conventional antibiotics. Consequently, discovering novel antimicrobial agents with potent antibacterial and antibiofilm activity has become a hotspot in recent years. Herein, the research first reported the remarkable inhibitory activity of AZD-5991, a selective Mcl-1 inhibitor, against S. aureus. The MIC50 and MIC90 values of AZD-5991 against S. aureus were 12.5 µM, and significant growth inhibition was observed at a subinhibitory concentration of 1/2 × MIC. Additionally, AZD-5991 exhibited bactericidal activity and a robust capacity for inhibiting S. aureus biofilm formation, with minimal cytotoxicity toward host cell lines. Membrane permeability assays revealed that AZD-5991 compromised S. aureus cell membrane integrity, while bacterial phospholipid components were found to neutralize the antibacterial activity of AZD-5991. Moreover, whole-genome sequencing and proteomic analysis were also applied to gain insights into the possible impact of AZD-5991 on the fatty metabolism of S. aureus. Furthermore, the antibacterial activity of AZD-5991 was remarkably declined by exogenous fatty acids linoleic acid (C18:2Δ9,12) and arachidonic acid (C20:4Δ5,8,11,14). Lastly, the biolayer interferometry assay supported the direct interaction of AZD-5991 with FabI, a key protein essential for bacterial growth and fatty acid metabolism. Conclusively, this study demonstrates that AZD-5991 inhibits S. aureus planktonic growth and biofilm formation by disrupting cell membrane integrity and targeting FabI. These findings position AZD-5991 as a promising novel antibiotic candidate for treating S. aureus infections resistant to traditional clinical antibiotics. Graphical Abstract |
| format | Article |
| id | doaj-art-c86d97c1a3464b0fa642e5b2c7c67367 |
| institution | Kabale University |
| issn | 1471-2180 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Microbiology |
| spelling | doaj-art-c86d97c1a3464b0fa642e5b2c7c673672025-08-20T04:01:25ZengBMCBMC Microbiology1471-21802025-07-0125111510.1186/s12866-025-04104-2Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabIYuanyuan Tang0Han Deng1Zhichao Xu2Zhijian Yu3Yong Xiang4Zewen Wen5Shiqing Han6Zhong Chen7Tieying Hou8College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech UniversityCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech UniversityCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech UniversityGuangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Affiliated Nanshan Hospital of Shenzhen UniversityMarketing Department, Guangzhou Branch Varian Medical Equipment Trading (Beijing) Corp.Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Affiliated Nanshan Hospital of Shenzhen UniversityCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech UniversityGuangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Affiliated Nanshan Hospital of Shenzhen UniversityGuangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Affiliated Nanshan Hospital of Shenzhen UniversityAbstract Staphylococcus aureus infections have emerged as a global public health threat. Two key factors—drug resistance and biofilm formation—substantially impair the efficacy of the antimicrobial treatment for S. aureus infections using conventional antibiotics. Consequently, discovering novel antimicrobial agents with potent antibacterial and antibiofilm activity has become a hotspot in recent years. Herein, the research first reported the remarkable inhibitory activity of AZD-5991, a selective Mcl-1 inhibitor, against S. aureus. The MIC50 and MIC90 values of AZD-5991 against S. aureus were 12.5 µM, and significant growth inhibition was observed at a subinhibitory concentration of 1/2 × MIC. Additionally, AZD-5991 exhibited bactericidal activity and a robust capacity for inhibiting S. aureus biofilm formation, with minimal cytotoxicity toward host cell lines. Membrane permeability assays revealed that AZD-5991 compromised S. aureus cell membrane integrity, while bacterial phospholipid components were found to neutralize the antibacterial activity of AZD-5991. Moreover, whole-genome sequencing and proteomic analysis were also applied to gain insights into the possible impact of AZD-5991 on the fatty metabolism of S. aureus. Furthermore, the antibacterial activity of AZD-5991 was remarkably declined by exogenous fatty acids linoleic acid (C18:2Δ9,12) and arachidonic acid (C20:4Δ5,8,11,14). Lastly, the biolayer interferometry assay supported the direct interaction of AZD-5991 with FabI, a key protein essential for bacterial growth and fatty acid metabolism. Conclusively, this study demonstrates that AZD-5991 inhibits S. aureus planktonic growth and biofilm formation by disrupting cell membrane integrity and targeting FabI. These findings position AZD-5991 as a promising novel antibiotic candidate for treating S. aureus infections resistant to traditional clinical antibiotics. Graphical Abstracthttps://doi.org/10.1186/s12866-025-04104-2Staphylococcus aureusAntimicrobial activityAZD-5991BiofilmFabI |
| spellingShingle | Yuanyuan Tang Han Deng Zhichao Xu Zhijian Yu Yong Xiang Zewen Wen Shiqing Han Zhong Chen Tieying Hou Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI BMC Microbiology Staphylococcus aureus Antimicrobial activity AZD-5991 Biofilm FabI |
| title | Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI |
| title_full | Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI |
| title_fullStr | Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI |
| title_full_unstemmed | Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI |
| title_short | Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI |
| title_sort | repurposing azd 5991 for inhibiting growth and biofilm formation of staphylococcus aureus by disrupting the cell membrane and targeting fabi |
| topic | Staphylococcus aureus Antimicrobial activity AZD-5991 Biofilm FabI |
| url | https://doi.org/10.1186/s12866-025-04104-2 |
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