In vitro Antimicrobial Activity Profile of Modified Pyrimidine Nucleosides Derivatives

Abstract

Background: The increase in prevalence of antimicrobial-resistant bacteria (ARB) is currently a serious threat, thus there is a need for new classes antimicrobial compounds to combat infections caused by these ARB. The growth inhibition ability of derivatives of the components of nucleic acids has been well-characterized but not for its antimicrobial characteristics. Aims: To evaluate in vitro antimicrobial activity profile of modified pyrimidine nucleosides derivatives. Methodology: Modified nucleosides arabinofuranosylcytosine (cytarabine, ara-C), [1-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-4-(1,2,4-triazol-1-yl)]uracil (TTU), and nucleotides cytarabine-5′-monophosphate (ara-CMP), and O2,2′-cyclocytidine-5′-monophosphate (cyclocytidine monophosphate, cyclo-CMP) were synthetized and subsequentially checked for antibacterial activity. Bacterial cells characteristics were assessed by antiproliferative and the production of intracellular reactive oxygen species (ROS) assays. Results: It was found that modified nucleosides ara-C, and TTU, and nucleotides ara-CMP, and cyclo-CMP were able to inhibit Escherichia coli, Sarcina lutea, Bacillus cereus, and Proteus mirabilis strains in a time and dose dependent manner via killing kinetics assay. Gram-negative (E. coli and P. mirabilis) bacteria stains were more sensitive to the exposure of TTU and cyclo-CMP and less sensitive to the exposure of ara-C and ara-CMP compared to gram-positive ones. The most effective cells growth inhibitor for gram-positive strains (S. lutea, B. cereus) was ara-CMP with ED50 = 5.2•10-5 M and 3.1•10-4 M, respectively. Sarcina lutea appeared to be the most sensitive bacteria strain to the exposure of all studied compounds. It was demonstrated that studied modified pyrimidine nucleosides derivatives enhanced the production of intracellular ROS over time (validated via DCFA-DA probe assay). Conclusion: This study has revealed the mechanism of action of cytarabine, cyclocytidine monophosphate, and TTU as an antimicrobial agent for the first time, and has shown that these pyrimidine derivatives enhanced might be able to combat infections caused by Escherichia coli, Sarcina lutea, Bacillus cereus, and Proteus mirabilis in the future.