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Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI
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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.
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Metadata
- Authors
- Tang, Y., Deng, H., Xu, Z., Yu, Z., Xiang, Y., Wen, Z., Han, S., Chen, Z., & Hou, T.
- Affiliations
- Nanjing Tech University (CN)
- Shenzhen University (CN)
- Corresponding author
- Han, Shiqing
- Venue
- BMC Microbiology
- Published
- 2025-07-02
- Volume
- 25
- Issue
- 1
- Pages
- 393-393
- ISSN
- 1471-2180 (ISSN-L)
- PMC
- PMC12220326
- OpenAlex
- W4411917844
- Cited by
- 4
- References
- 2
- Citations by year
- 2026: 3 · 2025: 1
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Microbiology (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Shenzhen Nanshan District Scientific Research Program of the People’s Republic of China (NS2024007, NS2023008, NSZD2024023, NSZD2024032, NS2022046, NS2024001Z, NS2024038)
- National Natural Science Foundation of China (82172283)
- Basic and Applied Basic Research Foundation of Guangdong Province (2022A1515110096, 2024A1515013276)
- Sanming Project of Medicine in Shenzen Municipality (SMZ202303037)
- Science, Technology and Innovation Commission of Shenzhen Municipality of basic research funds (JCYJ20220530141614034, JCYJ20240813114503005)
- Shenzhen Key Medical Discipline Construction Fund (SZXK06162)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antimicrobial agents and applications
- Keywords
- Staphylococcus aureus, antibacterial activity, antibiofilm activity, biofilm formation, plasma membrane integrity, FabI, fatty acid metabolism, Mcl-1 inhibitors, drug repurposing, linoleic acid, arachidonic acid, bacterial fatty acids, drug resistance, bactericidal activity
- MeSH terms
- Anti-Bacterial Agents, Bacterial Proteins, Cell Membrane, Humans, Microbial Sensitivity Tests, Staphylococcal Infections, Staphylococcus aureus, Biofilms
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