Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection
A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound <b>9</b> was found to be the most active antibacterial derivativ...
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| Format: | Article |
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MDPI AG
2022-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/3/931 |
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| author | Han-Qing Fang Jie Zeng Shou-Kai Wang Xiao Wang Fang Chen Bo Li Jie Liu Zhen Jin Ya-Hong Liu You-Zhi Tang |
| author_facet | Han-Qing Fang Jie Zeng Shou-Kai Wang Xiao Wang Fang Chen Bo Li Jie Liu Zhen Jin Ya-Hong Liu You-Zhi Tang |
| author_sort | Han-Qing Fang |
| collection | DOAJ |
| description | A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound <b>9</b> was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound <b>9</b> had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound <b>9</b> (K<sub>D</sub> = 1.77 × 10<sup>−8</sup> M) showed stronger affinity to the 50S ribosome than tiamulin (K<sub>D</sub> = 2.50 × 10<sup>−8</sup> M). The antibacterial activity of compound <b>9</b> was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log<sub>10</sub> CFU/mL), and compound <b>9</b> performed a treatment effect (~1.3 log<sub>10</sub> CFU/mL). In addition, compound <b>9</b> was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC<sub>50</sub> = 2.92 μg/mL). |
| first_indexed | 2024-03-09T23:27:54Z |
| format | Article |
| id | doaj.art-08e07b28fbdd43bd82d413dd0f7b51b4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T23:27:54Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-08e07b28fbdd43bd82d413dd0f7b51b42023-11-23T17:14:56ZengMDPI AGMolecules1420-30492022-01-0127393110.3390/molecules27030931Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA InfectionHan-Qing Fang0Jie Zeng1Shou-Kai Wang2Xiao Wang3Fang Chen4Bo Li5Jie Liu6Zhen Jin7Ya-Hong Liu8You-Zhi Tang9Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaGuangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaGuangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaGuangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaGuangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaGuangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaGuangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaGuangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaGuangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaGuangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaA series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound <b>9</b> was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound <b>9</b> had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound <b>9</b> (K<sub>D</sub> = 1.77 × 10<sup>−8</sup> M) showed stronger affinity to the 50S ribosome than tiamulin (K<sub>D</sub> = 2.50 × 10<sup>−8</sup> M). The antibacterial activity of compound <b>9</b> was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log<sub>10</sub> CFU/mL), and compound <b>9</b> performed a treatment effect (~1.3 log<sub>10</sub> CFU/mL). In addition, compound <b>9</b> was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC<sub>50</sub> = 2.92 μg/mL).https://www.mdpi.com/1420-3049/27/3/931antibacterial activityMRSApleuromutilinSPR50S ribosome |
| spellingShingle | Han-Qing Fang Jie Zeng Shou-Kai Wang Xiao Wang Fang Chen Bo Li Jie Liu Zhen Jin Ya-Hong Liu You-Zhi Tang Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection Molecules antibacterial activity MRSA pleuromutilin SPR 50S ribosome |
| title | Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection |
| title_full | Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection |
| title_fullStr | Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection |
| title_full_unstemmed | Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection |
| title_short | Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection |
| title_sort | discovery of novel pleuromutilin derivatives as potent antibacterial agents for the treatment of mrsa infection |
| topic | antibacterial activity MRSA pleuromutilin SPR 50S ribosome |
| url | https://www.mdpi.com/1420-3049/27/3/931 |
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