Nucleoside Analogues as Antibacterial Agents

Abstract

The rapid increase in antibiotic-resistant bacteria has emphasized the urgent need to identify new treatments for bacterial infections. One attractive approach, reducing the need for expensive and time-consuming clinical trials, is to repurpose existing clinically approved compounds for use as antibacterial agents. Nucleoside analogues are commonly used for treating viral and fungal infections, as well as for treating cancers, but have received relatively little attention as treatments for bacterial infections. However, a significant number of clinically approved derivatives of both pyrimidines and purines including halogenated, thiolated, and azolated compounds have been shown to have antibacterial activity. In the small number of studies carried out to date, such compounds have shown promise in treating bacterial infections. Here, we review the mechanisms of action and antibacterial activities of nucleoside analogues that can potentially be repurposed for treating infections as well as considering possible limitations in their usage.

Keywords: antibacterial agents; antibiotic resistance; antimicrobial; multidrug-resistant bacteria; purine analogues; pyrimidine analogues; repurposed antibiotics.

Figure 1

Pathways by which pyrimidine and purine analogues are metabolized and become incorporated into DNA and RNA. Inhibition of enzymes by nucleoside analogues and their metabolites is also shown (⊣). (A) Pyrimidine analogues. (B) Purine analogues. Abbreviations: HPRT, hypoxanthine-guanine phosphoribosyl transferase; IMP, inosine monophosphate; RNR, ribonucleotide reductase; TK, thymidylate kinase; TMK, deoxythymidine monophosphate kinase; TS, thymidylate synthase; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; XMP, xanthosine monophosphate.

Figure 2

Structures of pyrimidines, purines, and their analogues, with substituted atoms highlighted. (A) Deoxycytidine and its analogue. (B) Thymidine and its analogues. (C) Cytosine, uracil, and fluorinated pyrimidines. (D) Hypoxanthine, guanine, and their analogues.