The Synthesis and Biological Evaluation of a Novel Pleuromutilin Derivative Containing a 4-Fluorophenyl Group Targeting MRSA
The pleuromutilin derivative, the compound PL-W, was synthesized by introducing a 4-fluorophenyl group at the C21 position and selected for comprehensive antibacterial evaluation. PL-W demonstrated notable antibacterial activity against methicillin-resistant <i>Staphylococcus aureus</i>...
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2025-05-01
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| author | Yongfei Wang Yi Zhao Haiting Wang Bo Liu Shuangyi Zhang Yuan Liu Ruinan Li Tao Zhang Surong Hasi Wei Mao |
| author_facet | Yongfei Wang Yi Zhao Haiting Wang Bo Liu Shuangyi Zhang Yuan Liu Ruinan Li Tao Zhang Surong Hasi Wei Mao |
| author_sort | Yongfei Wang |
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| description | The pleuromutilin derivative, the compound PL-W, was synthesized by introducing a 4-fluorophenyl group at the C21 position and selected for comprehensive antibacterial evaluation. PL-W demonstrated notable antibacterial activity against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), with a minimum inhibitory concentration (MIC) of 0.03125 µg/mL, which is significantly lower than that of tiamulin (0.5 µg/mL). Crystal violet (CV) staining revealed that it inhibited MRSA biofilm formation and electron microscopy revealed that it disrupted bacterial cell division and, possibly, the synthesis of essential cell wall proteins. In both in vivo models, PL-W exhibited excellent performance. In the <i>Galleria mellonella</i> infection model, treatment with different concentrations of PL-W increased the survival rate from 20% to 90% and significantly reduced the bacterial load. In the mouse model of MRSA pneumonia, a 10 mg/kg dose of PL-W increased the survival rate to 70%, decreased the bacterial load in the lungs, and alleviated inflammatory damage. Molecular docking studies indicated that PL-W had a similar docking pose and comparable binding affinity to that of lefamulin, with hydrogen bond interactions that are crucial for binding to the peptidyl transferase center (PTC). Moreover, it demonstrated no significant reduction in cell viability in HepG2 and HEK293 cells, even at high concentrations (≤50 µg/mL). Overall, PL-W shows significant potential as a novel anti-MRSA agent owing to its potent in vitro and in vivo activities and low cytotoxicity. |
| format | Article |
| id | doaj-art-d08ac3b105de4b67abba9458d0120195 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-d08ac3b105de4b67abba9458d01201952025-08-20T03:11:32ZengMDPI AGMolecules1420-30492025-05-013011236610.3390/molecules30112366The Synthesis and Biological Evaluation of a Novel Pleuromutilin Derivative Containing a 4-Fluorophenyl Group Targeting MRSAYongfei Wang0Yi Zhao1Haiting Wang2Bo Liu3Shuangyi Zhang4Yuan Liu5Ruinan Li6Tao Zhang7Surong Hasi8Wei Mao9Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Hohhot 010011, ChinaLaboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Hohhot 010011, ChinaShandong Provincial Animal and Poultry Green Health Products Creation Engineering Laboratory, Institute of Poultry Science, Shandong Academy of Agricultural Science, Jinan 250100, ChinaLaboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Hohhot 010011, ChinaLaboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Hohhot 010011, ChinaLaboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Hohhot 010011, ChinaLaboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Hohhot 010011, ChinaLaboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Hohhot 010011, ChinaLaboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Hohhot 010011, ChinaLaboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Hohhot 010011, ChinaThe pleuromutilin derivative, the compound PL-W, was synthesized by introducing a 4-fluorophenyl group at the C21 position and selected for comprehensive antibacterial evaluation. PL-W demonstrated notable antibacterial activity against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), with a minimum inhibitory concentration (MIC) of 0.03125 µg/mL, which is significantly lower than that of tiamulin (0.5 µg/mL). Crystal violet (CV) staining revealed that it inhibited MRSA biofilm formation and electron microscopy revealed that it disrupted bacterial cell division and, possibly, the synthesis of essential cell wall proteins. In both in vivo models, PL-W exhibited excellent performance. In the <i>Galleria mellonella</i> infection model, treatment with different concentrations of PL-W increased the survival rate from 20% to 90% and significantly reduced the bacterial load. In the mouse model of MRSA pneumonia, a 10 mg/kg dose of PL-W increased the survival rate to 70%, decreased the bacterial load in the lungs, and alleviated inflammatory damage. Molecular docking studies indicated that PL-W had a similar docking pose and comparable binding affinity to that of lefamulin, with hydrogen bond interactions that are crucial for binding to the peptidyl transferase center (PTC). Moreover, it demonstrated no significant reduction in cell viability in HepG2 and HEK293 cells, even at high concentrations (≤50 µg/mL). Overall, PL-W shows significant potential as a novel anti-MRSA agent owing to its potent in vitro and in vivo activities and low cytotoxicity.https://www.mdpi.com/1420-3049/30/11/2366pleuromutilin derivativemethicillin-resistant <i>Staphylococcus aureus</i>antibacterial activitymolecular docking |
| spellingShingle | Yongfei Wang Yi Zhao Haiting Wang Bo Liu Shuangyi Zhang Yuan Liu Ruinan Li Tao Zhang Surong Hasi Wei Mao The Synthesis and Biological Evaluation of a Novel Pleuromutilin Derivative Containing a 4-Fluorophenyl Group Targeting MRSA Molecules pleuromutilin derivative methicillin-resistant <i>Staphylococcus aureus</i> antibacterial activity molecular docking |
| title | The Synthesis and Biological Evaluation of a Novel Pleuromutilin Derivative Containing a 4-Fluorophenyl Group Targeting MRSA |
| title_full | The Synthesis and Biological Evaluation of a Novel Pleuromutilin Derivative Containing a 4-Fluorophenyl Group Targeting MRSA |
| title_fullStr | The Synthesis and Biological Evaluation of a Novel Pleuromutilin Derivative Containing a 4-Fluorophenyl Group Targeting MRSA |
| title_full_unstemmed | The Synthesis and Biological Evaluation of a Novel Pleuromutilin Derivative Containing a 4-Fluorophenyl Group Targeting MRSA |
| title_short | The Synthesis and Biological Evaluation of a Novel Pleuromutilin Derivative Containing a 4-Fluorophenyl Group Targeting MRSA |
| title_sort | synthesis and biological evaluation of a novel pleuromutilin derivative containing a 4 fluorophenyl group targeting mrsa |
| topic | pleuromutilin derivative methicillin-resistant <i>Staphylococcus aureus</i> antibacterial activity molecular docking |
| url | https://www.mdpi.com/1420-3049/30/11/2366 |
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