Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

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

Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China

Author to whom correspondence should be addressed.

Academic Editor: Michio Kurosu

Molecules 2022, 27(3), 931; https://doi.org/10.3390/molecules27030931

Received: 29 December 2021 / Revised: 22 January 2022 / Accepted: 26 January 2022 / Published: 29 January 2022

(This article belongs to the Special Issue Antibacterial Agents 2021)

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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 (K_D = 1.77 × 10⁻⁸ M) showed stronger affinity to the 50S ribosome than tiamulin (K_D = 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). View Full-Text

Keywords: antibacterial activity; MRSA; pleuromutilin; SPR; 50S ribosome

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MDPI and ACS Style

Fang, H.-Q.; Zeng, J.; Wang, S.-K.; Wang, X.; Chen, F.; Li, B.; Liu, J.; Jin, Z.; Liu, Y.-H.; Tang, Y.-Z. Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection. Molecules 2022, 27, 931. https://doi.org/10.3390/molecules27030931

AMA Style

Fang H-Q, Zeng J, Wang S-K, Wang X, Chen F, Li B, Liu J, Jin Z, Liu Y-H, Tang Y-Z. Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection. Molecules. 2022; 27(3):931. https://doi.org/10.3390/molecules27030931

Chicago/Turabian Style

Fang, Han-Qing, Jie Zeng, Shou-Kai Wang, Xiao Wang, Fang Chen, Bo Li, Jie Liu, Zhen Jin, Ya-Hong Liu, and You-Zhi Tang. 2022. "Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection" Molecules 27, no. 3: 931. https://doi.org/10.3390/molecules27030931

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Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

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