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Pyrimidine nucleoside: inspiration for novel antimicrobial agent
Binjie Xu1,2, Pengyu Li2, Jiping Liu1
1Department of Pharmacology, School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China.
Frontiers in Pharmacology
|March 23, 2026
Summary
Pyrimidine nucleosides show promise for combating antimicrobial resistance (AMR). Modifications enhance antibacterial activity, but clinical translation requires understanding their metabolism and overcoming toxicity barriers.
Area of Science:
- * Medicinal Chemistry and Pharmacology
- * Microbiology and Infectious Diseases
Background:
- * Antimicrobial resistance (AMR) is a critical global health threat, necessitating novel therapeutic strategies.
- * Drug repurposing, particularly using pyrimidine nucleosides, offers a viable approach due to their adaptable structures and potential for broad therapeutic applications.
- * Current research on pyrimidine nucleoside derivatives faces hurdles in structure-activity relationships (SAR), metabolism-efficacy links, and clinical implementation.
Purpose of the Study:
- * To systematically review and categorize pyrimidine nucleoside derivatives (cytosine and uracil/thymine analogs) for antibacterial applications.
- * To analyze the impact of structural modifications (e.g., lipidation, selenylation) on antibacterial activity, target binding, membrane permeability, and metabolic stability.
- * To elucidate the metabolic activation mechanism of these prodrugs and identify key barriers to clinical translation.
Main Methods:
- * Comprehensive literature review and analysis of existing studies on pyrimidine nucleoside derivatives.
- * Categorization of derivatives based on their core nucleobase structure (cytosine vs. uracil/thymine).
- * Examination of structure-activity relationships (SAR) and metabolic pathways influencing antibacterial efficacy.
Main Results:
- * Structural modifications, including lipidation and selenylation, significantly modulate the antibacterial potency of pyrimidine nucleoside derivatives.
- * These compounds function as prodrugs requiring intracellular enzymatic phosphorylation to active metabolites that inhibit nucleic acid synthesis.
- * Efficacy is intrinsically linked to intracellular enzyme levels and activity, highlighting a crucial metabolic dependency.
- * Key challenges for clinical translation include host toxicity, narrow antibacterial spectrum, and limited research into AMR mechanisms.
Conclusions:
- * A systematic framework integrating SAR and metabolic insights is proposed for developing novel pyrimidine nucleoside antibacterial agents.
- * Targeted optimization strategies, such as enzyme-guided modifications and combination therapies, are crucial for overcoming clinical translation barriers.
- * This review provides a foundation for advancing pyrimidine nucleoside development to combat the global AMR crisis.
Keywords:
antibacterial agentsdrug resistancenucleosidespyrimidine derivativesstructure-activity relationshipMore Related Videos
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