# Pyrimidine nucleoside: inspiration for novel antimicrobial agent

## TL;DR

This review explores how pyrimidine nucleosides can be modified to create new antimicrobial agents, addressing challenges in drug development and resistance.

## Contribution

The paper introduces a systematic framework for developing pyrimidine nucleosides by integrating structure-activity and metabolic mechanism research.

## Key findings

- Pyrimidine nucleosides require intracellular phosphorylation to become active antibacterial agents.
- Structural modifications like lipidation and selenylation influence antibacterial activity and metabolic stability.
- Clinical translation barriers include host toxicity and narrow antimicrobial spectrum.

## Abstract

Antimicrobial resistance (AMR) is a worsening global health crisis, with drug repurposing emerging as a key mitigation strategy. Pyrimidine nucleosides are promising antibacterial scaffolds due to their easily modifiable structures and multi-therapeutic potential. However, related research faces challenges, including fragmented structure-activity relationships (SAR), unclear metabolism-efficacy correlations, and limited clinical translation strategies. This review categorizes these derivatives into cytosine and uracil/thymine analogs. It analyzes how lipidation, selenylation, and other structural modifications regulate antibacterial activity by modulating target binding, membrane permeability, and metabolic stability. Crucially, it elucidates their metabolic activation mechanism. As prodrugs, these derivatives require intracellular enzymatic phosphorylation to form active metabolites that inhibit nucleic acid synthesis, and their efficacy is dependent on intracellular enzyme levels and activity. Additionally, the review identifies core clinical translation barriers (host toxicity, narrow spectrum, insufficient AMR research) and proposes targeted optimization strategies (e.g., enzyme-guided modification and combination therapy). By integrating disparate structure-activity relationship and metabolic mechanism research, this work provides a novel systematic framework for developing pyrimidine nucleosides. Furthermore, it offers critical support to address the global antimicrobial resistance (AMR) crisis.

Illustration showing the chemical modification of pyrimidine nucleoside structures, highlighting modified groups for designing antibacterial compounds, with the title “Can pyrimidine nucleoside compounds serve as antibacterial weapons?” set against a background of stylized bacteria and laboratory equipment.