Molecular mechanism of crisaborole combined with erythromycin against methicillin-resistant Staphylococcus aureus in vivo and in vitro
The widespread presence of methicillin-resistant Staphylococcus aureus (MRSA) severely threatens convenient therapeutic options in the postantibiotic era. The use of combinations of existing drugs at this stage may be a viable strategy for dealing with complex drug-resistant MRSA infections. An chec...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1503515/full |
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| author | Yinuo Zou Yinuo Zou Lei Yu Jinjing Xue Tianqi Fang Liping Sun Jianfeng Wang Minhe Cui Peng Zhang Yonglin Zhou |
| author_facet | Yinuo Zou Yinuo Zou Lei Yu Jinjing Xue Tianqi Fang Liping Sun Jianfeng Wang Minhe Cui Peng Zhang Yonglin Zhou |
| author_sort | Yinuo Zou |
| collection | DOAJ |
| description | The widespread presence of methicillin-resistant Staphylococcus aureus (MRSA) severely threatens convenient therapeutic options in the postantibiotic era. The use of combinations of existing drugs at this stage may be a viable strategy for dealing with complex drug-resistant MRSA infections. An checkerboard MIC (Minimum Inhibitory Concentration) assay, growth curve assay, bactericidal test and scanning electron microscope (SEM) assays were performed to determine whether crisaborole (AN2728), a PDE4 inhibitor for treating atopic dermatitis (AD), produced bactericidal effect with different antibiotics. Here, we identified (AN2728) produced a significant synergistic bactericidal effect with erythromycin, cefuroxime and rifampicin against different bacterial strains of Staphylococcus aureus (S. aureus), especially MRSA (FIC < 0.5) (p < 0.05). Transcriptome analysis, bacterial biofilm assay and several kit assays revealed that AN2728 could also simultaneously affect the membrane and transporter capacity of MRSA. Moreover, in a mouse skin infection model of MRSA, the combination of AN2728 and erythromycin showed remarkable treatment benefits, as shown by significantly reduced bacterial loading (p < 0.05), pathological lesions of the skin and an obvious anti-inflammatory effect (p < 0.05). To our knowledge, this study is the first to establish that AN2728 can cooperate with antibiotics such as erythromycin to completely kill MRSA and that AN2728 can be used to extend the usage life of different antibiotics to address the inevitability of severe MRSA infection. |
| format | Article |
| id | doaj-art-3d3623082b3f4096841620dd9692cc3d |
| institution | OA Journals |
| issn | 1664-302X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj-art-3d3623082b3f4096841620dd9692cc3d2025-08-20T02:03:46ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2025-02-011610.3389/fmicb.2025.15035151503515Molecular mechanism of crisaborole combined with erythromycin against methicillin-resistant Staphylococcus aureus in vivo and in vitroYinuo Zou0Yinuo Zou1Lei Yu2Jinjing Xue3Tianqi Fang4Liping Sun5Jianfeng Wang6Minhe Cui7Peng Zhang8Yonglin Zhou9Thoracic Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, ChinaState 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 University, Changchun, ChinaDepartment of Physiology, Basic Medical College, Jilin University, Changchun, Jilin, ChinaKey Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, and School of Life Sciences, Ningxia University, Yinchuan, ChinaState 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 University, Changchun, ChinaAffiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, Jilin, ChinaState 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 University, Changchun, ChinaJilin Mushuo Breeding Co., Ltd, Changchun, Jilin, ChinaThoracic Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, ChinaKey Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, and School of Life Sciences, Ningxia University, Yinchuan, ChinaThe widespread presence of methicillin-resistant Staphylococcus aureus (MRSA) severely threatens convenient therapeutic options in the postantibiotic era. The use of combinations of existing drugs at this stage may be a viable strategy for dealing with complex drug-resistant MRSA infections. An checkerboard MIC (Minimum Inhibitory Concentration) assay, growth curve assay, bactericidal test and scanning electron microscope (SEM) assays were performed to determine whether crisaborole (AN2728), a PDE4 inhibitor for treating atopic dermatitis (AD), produced bactericidal effect with different antibiotics. Here, we identified (AN2728) produced a significant synergistic bactericidal effect with erythromycin, cefuroxime and rifampicin against different bacterial strains of Staphylococcus aureus (S. aureus), especially MRSA (FIC < 0.5) (p < 0.05). Transcriptome analysis, bacterial biofilm assay and several kit assays revealed that AN2728 could also simultaneously affect the membrane and transporter capacity of MRSA. Moreover, in a mouse skin infection model of MRSA, the combination of AN2728 and erythromycin showed remarkable treatment benefits, as shown by significantly reduced bacterial loading (p < 0.05), pathological lesions of the skin and an obvious anti-inflammatory effect (p < 0.05). To our knowledge, this study is the first to establish that AN2728 can cooperate with antibiotics such as erythromycin to completely kill MRSA and that AN2728 can be used to extend the usage life of different antibiotics to address the inevitability of severe MRSA infection.https://www.frontiersin.org/articles/10.3389/fmicb.2025.1503515/fullcrisaboroleerythromycinmethicillin-resistant Staphylococcus aureussynergistic effectskin infection |
| spellingShingle | Yinuo Zou Yinuo Zou Lei Yu Jinjing Xue Tianqi Fang Liping Sun Jianfeng Wang Minhe Cui Peng Zhang Yonglin Zhou Molecular mechanism of crisaborole combined with erythromycin against methicillin-resistant Staphylococcus aureus in vivo and in vitro Frontiers in Microbiology crisaborole erythromycin methicillin-resistant Staphylococcus aureus synergistic effect skin infection |
| title | Molecular mechanism of crisaborole combined with erythromycin against methicillin-resistant Staphylococcus aureus in vivo and in vitro |
| title_full | Molecular mechanism of crisaborole combined with erythromycin against methicillin-resistant Staphylococcus aureus in vivo and in vitro |
| title_fullStr | Molecular mechanism of crisaborole combined with erythromycin against methicillin-resistant Staphylococcus aureus in vivo and in vitro |
| title_full_unstemmed | Molecular mechanism of crisaborole combined with erythromycin against methicillin-resistant Staphylococcus aureus in vivo and in vitro |
| title_short | Molecular mechanism of crisaborole combined with erythromycin against methicillin-resistant Staphylococcus aureus in vivo and in vitro |
| title_sort | molecular mechanism of crisaborole combined with erythromycin against methicillin resistant staphylococcus aureus in vivo and in vitro |
| topic | crisaborole erythromycin methicillin-resistant Staphylococcus aureus synergistic effect skin infection |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1503515/full |
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