Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection |
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| Authors: | Han-Qing Fang Jie Zeng Shou-Kai Wang Xiao Wang Fang Chen Bo Li Jie Liu Zhen Jin Ya-Hong Liu You-Zhi Tang |
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| Institution: | 1.Guangdong 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, China; (H.-Q.F.); (J.Z.); (S.-K.W.); (X.W.); (F.C.); (B.L.); (J.L.); (Z.J.); (Y.-H.L.);2.Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China |
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| Abstract: | 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 9 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 9 had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound 9 (KD = 1.77 × 10−8 M) showed stronger affinity to the 50S ribosome than tiamulin (KD = 2.50 × 10−8 M). The antibacterial activity of compound 9 was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log10 CFU/mL), and compound 9 performed a treatment effect (~1.3 log10 CFU/mL). In addition, compound 9 was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC50 = 2.92 μg/mL). |
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| Keywords: | antibacterial activity MRSA pleuromutilin SPR 50S ribosome |
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