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.

Selected nucleos(t)ide-based prescribed drugs and their multi-target activity

“…Among them, the cytidine analogue gemcitabine was reported to be 6th on the list of broad-spectrum antivirals that show in vitro activities . Additionally, it was recently reported that several nucleoside analogues clinically approved as antivirals or antineoplastic agents also show antibacterial activity (Thomson and Lamont, 2019). Examples of such drugs include gemcitabine, zidovudine, 5-fluorouracil, floxuridine, idoxuridine and thiopurines.…”

“…Additionally, treatment with gemcitabine activates the expression of several IFN-stimulated genes (including CXCL10, IRF7, IRF9, IFIT1 or DDX58), the major effectors in innate immunity . Gemcitabine has also shown antibacterial activity against grampositive bacteria, such as Enterococcus, Listeria, Bacillus, and Staphylococcus, including multi-drug-resistant strains of Staphylococcus aureus (Thomson and Lamont, 2019;Jordheim et al, 2012;Sandrini et al, 2007). Unfortunately, one study revealed that the treated strains developed resistance to gemcitabine.…”

“…Such drugs belonging to the group of broad-spectrum antivirals are of particular interest since their pleiotropic effect may show activity against other viruses that have been undefined thus far (Ianevski et al, 2018. Recently, several approved antiviral and anticancer drugs from the nucleos(t)ide antimetabolite group have been reported to show newly discovered antiviral/antibacterial activities (Jordheim et al, 2013;Thomson and Lamont, 2019).…”

Antimicrobial peptide induced-stress rendersStaphylococcus aureussusceptible to toxic nucleoside analogues

“…Interestingly, these analogues have been proposed as an alternative to antibiotics as a consequence of resistance emergence (Thomson and Lamont, 2019). Nucleoside analogues have the advantage of being clinically approved for cancer therapies, but also as antiviral and antifungal treatments (Thomson and Lamont, 2019). Pyrimidine and purine analogues, as we use here, show potent antimicrobial activity against S. aureus in the past (Rogers and Perkins, 1960;Stickgold and Neuhaus, 1967;Jordheim et al, 2012a; Thomson and Lamont, 2019).…”

“…We hypothesised that the response to pexiganan sensitizes S. aureus against certain nucleoside antimetabolites or toxic nucleoside analogues. Interestingly, these analogues have been proposed as an alternative to antibiotics as a consequence of resistance emergence (Thomson and Lamont, 2019). Nucleoside analogues have the advantage of being clinically approved for cancer therapies, but also as antiviral and antifungal treatments (Thomson and Lamont, 2019).…”