Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-Hemolysin
Staphylococcus aureus (S.aureus) resistance, considered a dilemma for the clinical treatment of this bacterial infection, is becoming increasingly intractable. Novel anti-virulence strategies will undoubtedly provide a path forward in combating these resistant bacterial infections. Sortase A (SrtA),...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-09-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fmicb.2017.01715/full |
| _version_ | 1818566720173899776 |
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| author | Bing Zhang Bing Zhang Zihao Teng Xianhe Li Gejin Lu Xuming Deng Xuming Deng Xiaodi Niu Jianfeng Wang Jianfeng Wang |
| author_facet | Bing Zhang Bing Zhang Zihao Teng Xianhe Li Gejin Lu Xuming Deng Xuming Deng Xiaodi Niu Jianfeng Wang Jianfeng Wang |
| author_sort | Bing Zhang |
| collection | DOAJ |
| description | Staphylococcus aureus (S.aureus) resistance, considered a dilemma for the clinical treatment of this bacterial infection, is becoming increasingly intractable. Novel anti-virulence strategies will undoubtedly provide a path forward in combating these resistant bacterial infections. Sortase A (SrtA), an enzyme responsible for anchoring virulence-related surface proteins, and alpha-hemolysin (Hla), a pore-forming cytotoxin, have aroused great scientific interest, as they have been regarded as targets for promising agents against S. aureus infection. In this study, we discovered that chalcone, a natural small compound with little anti-S. aureus activity, could significantly inhibit SrtA activity with an IC50 of 53.15 μM and Hla hemolysis activity with an IC50 of 17.63 μM using a fluorescence resonance energy transfer (FRET) assay and a hemolysis assay, respectively. In addition, chalcone was proven to reduce protein A (SpA) display in intact bacteria, binding to fibronectin, formation of biofilm and S. aureus invasion. Chalcone could down-regulate the transcriptional levels of the hla gene and the agrA gene, thus leading to a reduction in the expression of Hla and significant protection against Hla-mediated A549 cell injury; more importantly, chalcone could also reduce mortality in infected mice. Additionally, molecular dynamics simulations and mutagenesis assays were used to identify the mechanism of chalcone against SrtA, which implied that the inhibitory activity lies in the bond between chalcone and SrtA residues Val168, Ile182, and Arg197. Taken together, the in vivo and in vitro experiments suggest that chalcone is a potential novel therapeutic compound for S. aureus infection via targeting SrtA and Hla. |
| first_indexed | 2024-12-14T01:57:13Z |
| format | Article |
| id | doaj.art-d3ed5c54f7e04809a93b4f08a3e58d8c |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-14T01:57:13Z |
| publishDate | 2017-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-d3ed5c54f7e04809a93b4f08a3e58d8c2022-12-21T23:21:09ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2017-09-01810.3389/fmicb.2017.01715276598Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-HemolysinBing Zhang0Bing Zhang1Zihao Teng2Xianhe Li3Gejin Lu4Xuming Deng5Xuming Deng6Xiaodi Niu7Jianfeng Wang8Jianfeng Wang9Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin UniversityChangchun, ChinaCenter of Infection and Immunity, The First Hospital, Jilin UniversityChangchun, ChinaKey Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin UniversityChangchun, ChinaKey Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin UniversityChangchun, ChinaKey Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin UniversityChangchun, ChinaKey Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin UniversityChangchun, ChinaCenter of Infection and Immunity, The First Hospital, Jilin UniversityChangchun, ChinaKey Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin UniversityChangchun, ChinaKey Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin UniversityChangchun, ChinaCenter of Infection and Immunity, The First Hospital, Jilin UniversityChangchun, ChinaStaphylococcus aureus (S.aureus) resistance, considered a dilemma for the clinical treatment of this bacterial infection, is becoming increasingly intractable. Novel anti-virulence strategies will undoubtedly provide a path forward in combating these resistant bacterial infections. Sortase A (SrtA), an enzyme responsible for anchoring virulence-related surface proteins, and alpha-hemolysin (Hla), a pore-forming cytotoxin, have aroused great scientific interest, as they have been regarded as targets for promising agents against S. aureus infection. In this study, we discovered that chalcone, a natural small compound with little anti-S. aureus activity, could significantly inhibit SrtA activity with an IC50 of 53.15 μM and Hla hemolysis activity with an IC50 of 17.63 μM using a fluorescence resonance energy transfer (FRET) assay and a hemolysis assay, respectively. In addition, chalcone was proven to reduce protein A (SpA) display in intact bacteria, binding to fibronectin, formation of biofilm and S. aureus invasion. Chalcone could down-regulate the transcriptional levels of the hla gene and the agrA gene, thus leading to a reduction in the expression of Hla and significant protection against Hla-mediated A549 cell injury; more importantly, chalcone could also reduce mortality in infected mice. Additionally, molecular dynamics simulations and mutagenesis assays were used to identify the mechanism of chalcone against SrtA, which implied that the inhibitory activity lies in the bond between chalcone and SrtA residues Val168, Ile182, and Arg197. Taken together, the in vivo and in vitro experiments suggest that chalcone is a potential novel therapeutic compound for S. aureus infection via targeting SrtA and Hla.http://journal.frontiersin.org/article/10.3389/fmicb.2017.01715/fullStaphylococcus aureussortase Aalpha-hemolysinchalconeinhibitor |
| spellingShingle | Bing Zhang Bing Zhang Zihao Teng Xianhe Li Gejin Lu Xuming Deng Xuming Deng Xiaodi Niu Jianfeng Wang Jianfeng Wang Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-Hemolysin Frontiers in Microbiology Staphylococcus aureus sortase A alpha-hemolysin chalcone inhibitor |
| title | Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-Hemolysin |
| title_full | Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-Hemolysin |
| title_fullStr | Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-Hemolysin |
| title_full_unstemmed | Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-Hemolysin |
| title_short | Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-Hemolysin |
| title_sort | chalcone attenuates staphylococcus aureus virulence by targeting sortase a and alpha hemolysin |
| topic | Staphylococcus aureus sortase A alpha-hemolysin chalcone inhibitor |
| url | http://journal.frontiersin.org/article/10.3389/fmicb.2017.01715/full |
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