ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Infectious Diseases
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1657973
This article is part of the Research TopicDesign and Synthesis of Natural Antibacterial DerivativesView all 4 articles
Synthesis and biological activity evaluation of a novel pleuromutilin derivative 22-((2-methyl-1-(1H-pyrrole-2-carboxamido)propan-2-yl)thio)-deoxypleuromutilin
Provisionally accepted
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
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Widespread antibiotic misuse has resulted in growing antimicrobial resistance, diminishing the clinical efficacy of existing antibiotics against resistant strains. Therefore, we designed and synthesized a novel pleuromutilin derivative PDP, and its antibacterial activities were evaluated in vitro and in vivo. PDP exhibited potent antibacterial activity against Gram-positive bacteria (MRSA, MRSE, S.aureus, S. agalactiae and S. dysgalactiae), demonstrating a remarkably low MIC of 0.008 μg/mL, which was superior to both reference drugs tiamulin and valnemulin. Moreover, compared to tiamulin, it displayed a slower rate of resistance development. Molecular docking results demonstrate that PDP exhibits favorable binding to the peptidyl transferase center. The inhibition of bacterial protein synthesis by PDP was indirectly demonstrated through GFP expression inhibition assays. Derivative PDP exhibited extremely low cytotoxicity and had low oral acute toxicity, with an LD50 exceeding 2000 mg/kg of body weight. When tested in a mouse model of systemic infection, PDP demonstrated superior efficacy to tiamulin and comparable activity to valnemulin. The bacterial carrier load indicated that PDP possessed significant efficacy in mitigating tissue damage resulting from MRSA infection in the lung, kidney, and liver.Consequently, PDP is a promising compound that may be useful for the development of therapeutic applications in the future.
Keywords: Pleuromutilin, PDP, Antibacterial activity, Toxicity, MRSA
Received: 02 Jul 2025; Accepted: 19 Aug 2025.
Copyright: © 2025 Li, Ma, Liu, Qin, Bai, Ge, Xu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jianyong Li, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
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