Nucleoside Analogs and Tuberculosis: New Weapons Against an Old Enemy

Abstract

Purine and pyrimidine nucleoside and nucleotide analogs have been extensively studied as anticancer and antiviral agents. In addition to this, they have recently shown great potential against Mycobacterium Tuberculosis, the causative agent of TB. TB ranks as the tenth most common cause of death in the world. The current treatment for TB infection is limited by side effects and cost of the drugs and most importantly by the development of resistance to the therapy. Therefore the development of novel drugs, capable of overcoming the drawbacks of the existing treatments, has become the focus of many research programs. In parallel to that, a tremendous effort has been made to elucidate the unique metabolism of this pathogen with the aim to identify new possible targets. This review presents the state of the art in nucleoside and nucleotide analogs in the treatment of TB. In particular, we report on the inhibitory activity of this class of compounds, both in enzymatic and whole-cell assays, providing a brief insight to which reported target these novel compounds are hitting.

Antibacterial Prodrugs to Overcome Bacterial Resistance

“…Pyrimidine nucleoside derivatives with a lengthy substituent at the C-5 position of the nucleobase were shown to have in vitro antimicrobial activity [45,46]. The mechanism of action is unclear, but it was shown that some derivatives selectively inhibit the microorganismic enzyme flavin-dependent thymidylate synthase (ThyX), an enzyme that is absent in mammals.…”

Synthesis and Antitubercular Activity of 4,5‐Disubstituted N1‐(5′‐deoxythymidin‐5′‐yl)‐1,2,3‐triazoles

“…Cases of TB due to lethal drug-resistant strains (DR-TB), multidrug-resistant strains (MDR-TB) and extensively drug-resistant strain (XDR-TB) are on the rise, which has warranted discovery of new TB treatment regimens and chemotherapeutic agents. [3][4][5][6] Design of nucleoside based drugs capable of interfering with mycobacterial purine and pyrimidine metabolic pathways is a promising approach towards the future of anti-TB therapy. [4][5][6][7][8][9] Two 5'-modified lead nucleoside antibiotics, SQ641 [5] and CPZEN-45 [6] are currently undergoing preclinical testing as an anti-TB agent (Figure 1).…”

“…[3][4][5][6] Design of nucleoside based drugs capable of interfering with mycobacterial purine and pyrimidine metabolic pathways is a promising approach towards the future of anti-TB therapy. [4][5][6][7][8][9] Two 5'-modified lead nucleoside antibiotics, SQ641 [5] and CPZEN-45 [6] are currently undergoing preclinical testing as an anti-TB agent (Figure 1). Substituted 1,2,3-triazoles have been considered as a privileged heterocyclic moiety owing to their indomitable biological potential [7] and ability to be linked to different pharmacophores to generate an array of new hybrid molecules with improved efficacy.…”

NAT/NCS2-hound: A Webserver for the detection and evolutionary classification of prokaryotic and eukaryotic nucleobase–cation symporters of the NAT/NCS2 family

“…Their additional function as providers of nitrogen/carbon source may also affect energy production, replication and protein synthesis through the salvage pathways for nucleotide synthesis [7,8] [9]. In addition to their important direct role on the central metabolism of the cell, these and other nucleobase transporters have attracted interest as potential targets of purine/pyrimidinebased antimicrobials that could either be selectively routed into target cells to act as antimetabolites or selectively inhibit an essential nucleobase transporter of the target cell [10][11][12][13][14] This protein family is one of the 18 known families of the APC superfamily [15] and represents a subset of APC families which conform to a distinct structural/mechanistic pattern. The NAT/NCS2 transporters consist of 14 transmembrane segments (TMs) divided in two inverted repeats (7+7) and arranged spatially into a core domain (TMs 1-4 and 8-11) and a gate domain (TMs 5-7 and 12-14) [16].…”