2,3-Dehydrokievitone combats methicillin-resistant Staphylococcus aureus infection by reducing alpha-hemolysin expression
Due to powerful drug resistance and fatal toxicity of methicillin-resistant Staphylococcus aureus (MRSA), therapeutic strategies against virulence factors present obvious advantages since no evolutionary pressure will induce bacterial resistance. Alpha-hemolysin (Hla) is an extracellular toxin secre...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2022.969215/full |
| _version_ | 1798038695661535232 |
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| author | Hangqian Yu Jingyu Liu Li Wang Li Wang Shuhan Guan Yajing Jin Jianze Zheng Hua Xiang Dacheng Wang Dianfeng Liu |
| author_facet | Hangqian Yu Jingyu Liu Li Wang Li Wang Shuhan Guan Yajing Jin Jianze Zheng Hua Xiang Dacheng Wang Dianfeng Liu |
| author_sort | Hangqian Yu |
| collection | DOAJ |
| description | Due to powerful drug resistance and fatal toxicity of methicillin-resistant Staphylococcus aureus (MRSA), therapeutic strategies against virulence factors present obvious advantages since no evolutionary pressure will induce bacterial resistance. Alpha-hemolysin (Hla) is an extracellular toxin secreted by Staphylococcus aureus and contributes to bacterial pathogenicity. Herein, we identified a natural product 2,3-dehydrokievitone (2,3-DHKV) for inhibiting Hla activity of MRSA strain USA300 but not affecting bacteria growth. 2,3-DHKV significantly decreased hemolysin expression in a dose-dependent manner, but it did not potently neutralize hemolysin activity. Subsequently, cellular thermal shift and heptamer formation assays confirmed that 2,3-DHK affects hemolytic activity through indirect binding to Hla. RT-qPCR and western blot revealed that 2,3-DHKV suppressed Hla expression at the mRNA and protein levels, and further decreased accessory gene regulator A (agrA) transcription levels. We also observed that 2,3-DHK significantly attenuated the damage of A549 cells by S. aureus and reduced the release of lactate dehydrogenase (LDH). Moreover, in the MRSA-induced pneumonia mouse model, 2,3-DHK treatment prolonged the life span of mice and reduced the bacterial load in the lungs, which significantly alleviated the damage to the lungs. In summary, this study proved that 2,3-DHK as a Hla inhibitor is a potential antivirulence agent against MRSA infection. |
| first_indexed | 2024-04-11T21:43:42Z |
| format | Article |
| id | doaj.art-45773d20e3f44587bf17545a408cc2c1 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-11T21:43:42Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-45773d20e3f44587bf17545a408cc2c12022-12-22T04:01:28ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2022-08-011310.3389/fmicb.2022.9692159692152,3-Dehydrokievitone combats methicillin-resistant Staphylococcus aureus infection by reducing alpha-hemolysin expressionHangqian Yu0Jingyu Liu1Li Wang2Li Wang3Shuhan Guan4Yajing Jin5Jianze Zheng6Hua Xiang7Dacheng Wang8Dianfeng Liu9College of Animal Science, Jilin University, Changchun, ChinaCollege of Animal Science, Jilin University, Changchun, ChinaCollege of Animal Science, Jilin University, Changchun, ChinaChangchun University of Chinese Medicine, Changchun, ChinaCollege of Animal Science, Jilin University, Changchun, ChinaCollege of Animal Science, Jilin University, Changchun, ChinaCollege of Animal Science, Jilin University, Changchun, ChinaCollege of Animal Medicine, Jilin Agricultural University, Changchun, ChinaCollege of Animal Science, Jilin University, Changchun, ChinaCollege of Animal Science, Jilin University, Changchun, ChinaDue to powerful drug resistance and fatal toxicity of methicillin-resistant Staphylococcus aureus (MRSA), therapeutic strategies against virulence factors present obvious advantages since no evolutionary pressure will induce bacterial resistance. Alpha-hemolysin (Hla) is an extracellular toxin secreted by Staphylococcus aureus and contributes to bacterial pathogenicity. Herein, we identified a natural product 2,3-dehydrokievitone (2,3-DHKV) for inhibiting Hla activity of MRSA strain USA300 but not affecting bacteria growth. 2,3-DHKV significantly decreased hemolysin expression in a dose-dependent manner, but it did not potently neutralize hemolysin activity. Subsequently, cellular thermal shift and heptamer formation assays confirmed that 2,3-DHK affects hemolytic activity through indirect binding to Hla. RT-qPCR and western blot revealed that 2,3-DHKV suppressed Hla expression at the mRNA and protein levels, and further decreased accessory gene regulator A (agrA) transcription levels. We also observed that 2,3-DHK significantly attenuated the damage of A549 cells by S. aureus and reduced the release of lactate dehydrogenase (LDH). Moreover, in the MRSA-induced pneumonia mouse model, 2,3-DHK treatment prolonged the life span of mice and reduced the bacterial load in the lungs, which significantly alleviated the damage to the lungs. In summary, this study proved that 2,3-DHK as a Hla inhibitor is a potential antivirulence agent against MRSA infection.https://www.frontiersin.org/articles/10.3389/fmicb.2022.969215/fullantivirulenceα-hemolysinmethicillin-resistant Staphylococcus aureuspneumonia2,3-dehydrokievitone |
| spellingShingle | Hangqian Yu Jingyu Liu Li Wang Li Wang Shuhan Guan Yajing Jin Jianze Zheng Hua Xiang Dacheng Wang Dianfeng Liu 2,3-Dehydrokievitone combats methicillin-resistant Staphylococcus aureus infection by reducing alpha-hemolysin expression Frontiers in Microbiology antivirulence α-hemolysin methicillin-resistant Staphylococcus aureus pneumonia 2,3-dehydrokievitone |
| title | 2,3-Dehydrokievitone combats methicillin-resistant Staphylococcus aureus infection by reducing alpha-hemolysin expression |
| title_full | 2,3-Dehydrokievitone combats methicillin-resistant Staphylococcus aureus infection by reducing alpha-hemolysin expression |
| title_fullStr | 2,3-Dehydrokievitone combats methicillin-resistant Staphylococcus aureus infection by reducing alpha-hemolysin expression |
| title_full_unstemmed | 2,3-Dehydrokievitone combats methicillin-resistant Staphylococcus aureus infection by reducing alpha-hemolysin expression |
| title_short | 2,3-Dehydrokievitone combats methicillin-resistant Staphylococcus aureus infection by reducing alpha-hemolysin expression |
| title_sort | 2 3 dehydrokievitone combats methicillin resistant staphylococcus aureus infection by reducing alpha hemolysin expression |
| topic | antivirulence α-hemolysin methicillin-resistant Staphylococcus aureus pneumonia 2,3-dehydrokievitone |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2022.969215/full |
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