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Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI
Open accessPreprint — published as 10.1186/s12866-025-04104-2 · Paper page
Abstract
Staphylococcus aureus infections have already become a major threat to public health worldwide. Drug resistance and biofilm formation are two critical factors that significantly affect the efficacy of the antimicrobial treatment of S. aureus infections using conventional antibiotics. Therefore, the discovery of novel antimicrobial agents with potent antibacterial and antibiofilm activity has become a hotspot in recent years. Here, we first demonstrated the remarkable inhibitory activity of AZD-5991, a selective Mcl-1 inhibitor, against S. aureus . The MIC 50 and MIC 90 of AZD-5991 against S. aureus were 12.5 μM, and AZD-5991 significantly inhibited the growth of S. aureus at a subinhibitory concentration of 1/2 × MIC. Besides, AZD-5991 displayed bactericidal activity and a robust capacity for inhibiting biofilm formation against S. aureus with very low drug toxicity against host cell lines. Our data demonstrated the disruption of S.aureus cell integrity by AZD-5991 through membrane permeability assays and the ingredients of the bacterial phospholipids could 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 significantly elevated by exogenous fatty acids linoleic acid (C18:2 Δ 9,12) and arachidonic acid (C20:4 Δ 5,8,11,14). Lastly, the biolayer interferometry assay supported the direct interaction of AZD-5991 with FabI, a necessary protein related closely to bacterial growth and fatty acid metabolism. Conclusively, this study suggests that AZD-5991 could inhibit the planktonic growth and biofilm formation of S. aureus by disrupting the cell membrane and targeting FabI. AZD-5991 might be a promising new antibiotic candidate for the antimicrobial treatment of S. aureus infections resistant to traditional clinical drugs. Graphical Abstract:
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Highly accurate protein structure prediction with AlphaFold
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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)
- Marketing Department, Guangzhou Branch Varian Medical Equipment Trading (Beijing) Corp., Guangzhou, 510623, China
- Corresponding author
- Han, Shiqing
- Venue
- BMC Microbiology
- Publisher
- openRxiv
- Published
- 2025-02-13
- Volume
- 25
- Issue
- 1
- Pages
- 393-393
- ISSN
- 1471-2180 (ISSN-L)
- PMC
- PMC12220326
- OpenAlex
- W4411917844
- Cited by
- 4
- References
- 1
- Citations by year
- 2026: 3 · 2025: 1
- FWCI
- 3.05
- 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
- National Natural Science Foundation of China (82172283)
- Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20220530141614034)
- Sanming Project of Medicine in Shenzhen (SMZ202303037)
- Basic and Applied Basic Research Foundation of Guangdong Province (2022A1515110096, 2024A1515013276, 2024A1515013276, 2022A1515110096)
- 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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