Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infections
Abstract The rising incidence of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global public health, highlighting the urgent need for novel therapies and treatments in clinical settings. Caseinolytic protease P (ClpP) serves as a key component of bacterial degradat...
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BMC
2025-06-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01306-2 |
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| author | Shufang Li Yan Zhang Jianfeng Wang Hongfa Lv Hongxia Ma Lingcong Kong Yonglin Zhou Jingmin Gu Wei Li Qiaoling Zhang |
| author_facet | Shufang Li Yan Zhang Jianfeng Wang Hongfa Lv Hongxia Ma Lingcong Kong Yonglin Zhou Jingmin Gu Wei Li Qiaoling Zhang |
| author_sort | Shufang Li |
| collection | DOAJ |
| description | Abstract The rising incidence of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global public health, highlighting the urgent need for novel therapies and treatments in clinical settings. Caseinolytic protease P (ClpP) serves as a key component of bacterial degradation systems, playing a crucial role in maintaining cellular homeostasis and contributing to pathogenicity. Targeting ClpP function inhibition has demonstrated potential in combating antibiotic resistance and offers a promising therapeutic strategy for treating S. aureus infections. In this study, coniferaldehyde (CA) was identified as a ClpP inhibitor through ClpP peptidase inhibition assay. CA reduced the hemolysis activity, protease hydrolysis and bacterial invasion ability via regulating the transcription of main virulence factors. Furthermore, CA treatment led to a decreased resistance of S. aureus to adverse stimuli, including heat, acidic pH, high osmotic environment, hydrogen peroxide and NaClO stress assays. Notably, CA enhanced the efficacy of the bactericidal antibiotic tigecycline against growing S. aureus in time-killing assays. Molecular simulations and mutagenesis analyses revealed that the amino acids M31 and G33 were critical for the interaction between CA and ClpP. Importantly, CA exhibited excellent protective efficacy against S. aureus pneumonia in murine infection models. Our findings confirm that CA is an effective ClpP inhibitor with potential as a therapeutic agent for S. aureus infections. Graphical Abstract |
| format | Article |
| id | doaj-art-e87c6e8db31b4e7ca4adc7fd1114a344 |
| institution | DOAJ |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-e87c6e8db31b4e7ca4adc7fd1114a3442025-08-20T03:03:37ZengBMCMolecular Medicine1528-36582025-06-0131111410.1186/s10020-025-01306-2Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infectionsShufang Li0Yan Zhang1Jianfeng Wang2Hongfa Lv3Hongxia Ma4Lingcong Kong5Yonglin Zhou6Jingmin Gu7Wei Li8Qiaoling Zhang9Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin UniversityHospital of Stomatology, Jilin UniversityState Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityState Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityCollege of Life Science, Jilin Agricultural UniversityCollege of Life Science, Jilin Agricultural UniversityKey Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, and School of Life Sciences, Ningxia UniversityState Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityDepartment of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin UniversityState Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityAbstract The rising incidence of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global public health, highlighting the urgent need for novel therapies and treatments in clinical settings. Caseinolytic protease P (ClpP) serves as a key component of bacterial degradation systems, playing a crucial role in maintaining cellular homeostasis and contributing to pathogenicity. Targeting ClpP function inhibition has demonstrated potential in combating antibiotic resistance and offers a promising therapeutic strategy for treating S. aureus infections. In this study, coniferaldehyde (CA) was identified as a ClpP inhibitor through ClpP peptidase inhibition assay. CA reduced the hemolysis activity, protease hydrolysis and bacterial invasion ability via regulating the transcription of main virulence factors. Furthermore, CA treatment led to a decreased resistance of S. aureus to adverse stimuli, including heat, acidic pH, high osmotic environment, hydrogen peroxide and NaClO stress assays. Notably, CA enhanced the efficacy of the bactericidal antibiotic tigecycline against growing S. aureus in time-killing assays. Molecular simulations and mutagenesis analyses revealed that the amino acids M31 and G33 were critical for the interaction between CA and ClpP. Importantly, CA exhibited excellent protective efficacy against S. aureus pneumonia in murine infection models. Our findings confirm that CA is an effective ClpP inhibitor with potential as a therapeutic agent for S. aureus infections. Graphical Abstracthttps://doi.org/10.1186/s10020-025-01306-2Staphylococcus aureusCaseinolytic proteaseConiferaldehydeMolecular simulationsVirulence |
| spellingShingle | Shufang Li Yan Zhang Jianfeng Wang Hongfa Lv Hongxia Ma Lingcong Kong Yonglin Zhou Jingmin Gu Wei Li Qiaoling Zhang Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infections Molecular Medicine Staphylococcus aureus Caseinolytic protease Coniferaldehyde Molecular simulations Virulence |
| title | Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infections |
| title_full | Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infections |
| title_fullStr | Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infections |
| title_full_unstemmed | Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infections |
| title_short | Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infections |
| title_sort | discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat staphylococcus aureus infections |
| topic | Staphylococcus aureus Caseinolytic protease Coniferaldehyde Molecular simulations Virulence |
| url | https://doi.org/10.1186/s10020-025-01306-2 |
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