Nucleoside Antibiotics: Definition, Biosynthesis and Examples

What are nucleoside antibiotics?

Nucleoside antibiotics are a class of compounds with antibiotic activity whose structure usually contains parts of nucleosides or nucleotides. Because nucleosides and nucleotides play an important role in basic cell metabolism, nucleoside antibiotics show a wide range of biological activities, including antibacterial, antifungal, antiviral, insecticidal, immunomodulatory and antitumor. This class of antibiotics usually consists of a heterocyclic nucleobase linked to a sugar molecule by a glycosidic bond, which has typical UV-visible light absorption properties.

Although nucleoside compounds are widely used in antiviral and anti-tumor therapy, their potential as antibacterial agents is still untapped. In recent years, there has been increasing research on the application of nucleoside antibiotics in the field of antibacterial, such as fluorouracil and cytarabine have been confirmed to have antibacterial activity, and have shown potential in treating bacterial infections in some studies. However, at present, no nucleoside antibiotics have been clinically approved for the treatment of bacterial infections, and the main obstacle is that the problems of toxicity and resistance have not been completely solved.

Nucleoside antibiotics have a long history of research, and scientists continue to explore their biosynthetic mechanisms. With the deepening of the understanding of the mechanism of action and biosynthetic pathways, it is expected that new and highly effective antibacterial drugs will be developed in the future.

Biosynthesis of nucleoside antibiotics

Nucleoside compounds have a unique structure, and many drugs used in the clinical treatment of viral infectious diseases and antibiotics used in agriculture for biological control of plant diseases and pests come from this family. The biosynthesis logic of nucleoside antibiotics is not complicated, generally building complex molecules from simple base blocks, but the synthesis process involves many complex multi-enzyme reactions. In recent years, several breakthroughs have been made in the field of nucleoside antibiotic biosynthesis, paving the way for targeted manufacturing of artificially designed nucleoside drugs through synthetic biology. Chen's research group discovered and analyzed the biosynthetic pathway of carbamoyl poly-oxamic acid (CPOAA) in polyoxin, and reconstructed the biosynthetic pathway of CPOAA in vitro, which enriched the synthetic components that can be edited by nucleoside antibiotics.

At the same time, they analyzed the special methylation modification of polyxycyclin nucleoside skeleton C-5 and the isomerization of C-2 hydroxyl group of pentostatin (PTN) and vidarabine (Ara-A), providing a reference for in vitro modification of nucleoside antibiotics. They also analyzed the catalytic basis of base-C-glucoside bonds between purine-associated C-nucleoside antibiotics ribose and pyrazofurin derivatives, such as formycin A (FOR-A) and pyrazofurin A (PRF-A), and tubercidin (tubercidin, PRF-A). N-glucoside linkage pathway between purine and glycoside, such nucleoside analogues as TBN. The elucidation of the assembly logic of these nucleoside antibiotics not only provides the enzymological basis for further understanding of the biosynthesis of related nucleoside antibiotics, but also helps to rationally design more hybrid nucleoside antibiotics through synthetic biology strategies.

Recently, they reported a targeted genome mining method to find and characterize the purine nucleoside antibiotics aristeromycin (ARM) and coformycin in micromonospora haikou DSM 45626 and Streptomyces citreus NBRC 13005. The biosynthetic pathway of COF has opened up a new way for rational search of purine antibiotics.

Nucleoside antibiotics mechanism of action

Nucleoside antibiotics have shown potential to treat bacterial infections by inhibiting key biosynthetic pathways in bacteria. For example, liposidomycins, a novel nucleoside antibiotic produced by Streptomyces, works by inhibiting the phosphate n-acetyllactoamine pentapeptide transferase in the synthesis of bacterial peptidoglycans. Capramasine A-G also show antibacterial activity by inhibiting the GLCACC-1-phosphotransferase WecA, which is the initial stage of cell wall synthesis of tuberculosis bacteria.

Tunicamycin exerts an antibacterial effect by inhibiting protein glycosylase (PGT), which is critical in the process of bacterial protein glycosylation. mureidomycin and muraymycin also work by inhibiting PGT, and muraymycins in particular have received much attention for their specific inhibition of MraY.

Nucleoside antibiotics at BOC Sciences

Nucleoside antibiotics examples

Miharamycins and amipurimycin

Peptidyl nucleoside antibiotics (PNAs) are generally composed of three structural units: core sugar skeleton, base and amino acid side chain. Under the background of the depletion of innovative antibacterial drug pipeline and the increasingly severe threat of drug-resistant bacteria, the complex and diverse structural characteristics and excellent activity of PNAs make them the source of innovation in the development of new antibiotics.

Miharamycins(A and B) and amipurimycin are two structurally related natural product PNAs. It was first isolated from Streptomyces novoguineensis and Streptomyces miharaensis by Japanese scientists in the 1960s and 1970s, respectively. This natural product not only has excellent anti-blast activity (10 to 20 ppm effective concentration), but also has good antibacterial, fungal and antiviral activity. This natural product contains 2-amino-purine bases and a complex 9-carbopyranose amino acid core (can be regarded as modified substituted D-alosaccharide) and is loaded with different amino acid side chains (cispentacin and arginine and N5-hydroxyarginine). miharamycins are distinguished from amipurimycin by their unique tetrahydrofuranopyranose ring. The good biological activity and complex molecular structure of Miharamycins have attracted the research interest of many scientists, especially synthetic chemists, but the complete synthesis of miharamycins has not been reported in the literature so far. Wang et al. achieved the first asymmetric total synthesis of miharamycin B and its biosynthetic precursors in 20 and 18 steps, respectively. This study has successfully opened up a new way to synthesize C-3 branched pyranoids, which can be used for the total synthesis of miharamycins and amipurimycin class natural products. The good compatibility of this route also provides a new idea for the pharmacochemistry research of this kind of PNAs.

Chemical structure of miharamycins(A and B) and amipurimycin. (Huang, W., 2022)

Puromycin

Puromycin is an aminucleoside antibiotic that replaces normal amino acids by imitating the 3'-end of aminoacylated tRNA (aa-tRNA), and is catalyzed by the ribosomal peptidyl transferase center (PTC) to incorporate into the C-terminal of the new chain., preventing the normal extension of the amino acid chain, leading to premature termination of translation and interfering with protein synthesis. The puromycin resistance gene (PuroR or Pac gene) encodes a puromycin-N-acetyltransferase (PAC) that acetylate the puromycin molecule, making cells resistant to puromycin.

Pentostatin and arabinofuranosyladenine

Pentostatin (PTN) and arabinofuranosyladenine (Ara-A) are purine nucleoside antibiotics used in the clinical treatment of hematological cancers and human DNA viral infections. PTN is characterized by its 1, 3-diazocyclic structure, while Ara-A is an adenosine analogue with differential isomerization at the C-2' hydroxyl group. The mechanism of biosynthesis of these molecules has long been unclear, and Wu et al. 's study reveals a special protective strategy for the biosynthesis of PTN and Ara-A. The results showed that a single gene cluster regulates the biosynthesis of PTN and Ara-A through two independent pathways, and purified REDOX reductase PenB is a reversible REDOX reductase in the last link of PTN biosynthesis. This study provides the first direct biochemical evidence that PTN protects Ara-A from deamination by selectively inhibiting host adenosine deaminase. It expands the understanding of natural product biosynthesis and provides a new direction for the targeted genome mining of Ara-A/PTN class antibiotics.

Tunicamycin

Tunicamycin was isolated by Tamura et al. from Micrococcus lysosuperficus and is a powerful inhibitor of peptidoglycan biosynthesis, the attachment of teichoic acid and Teichuronic acid to peptidoglycans, and protein N-glycosylation. It inhibits the growth and reproduction of Gram-positive bacteria, yeasts, fungi and viruses in vitro. It can also inhibit multiple biochemical functions, such as glycoprotein, collagen precollagen and peptidoglycan synthesis, IgA and IgE secretion activities in plasma cells, etc. Tunicamycin inhibits the N-acetylhexosamine (HexNAc) phosphotransferase family in bacteria and prevents the biosynthesis of peptidoglycans. Tunicamycin also inhibits N-acetylglucosamine (GlcNAc) phosphotransferase (GPT) in bacteria and eukaryotes, preventing the production of N-acetylglucosamine lipid intermediates. Tunicamycin has also been found to have anticancer activity.

Ascamycin and dealanylascamycin

Ascamycin is a 5'-O-sulfonamide ribonucleoside antibiotic produced by Streptomyces sp. JCM9888. It has selective antibacterial activity by inhibiting protein synthesis, mainly targeting bacteria of the genus Xanthomonas. In contrast, its derivative dealanyasmycin (DACM) shows a broader spectrum of antibacterial activity, including inhibition of Gram-positive and negative bacteria, and even killing certain parasites.

References

1. Wu, P., et al. An unusual protector-protégé strategy for the biosynthesis of purine nucleoside antibiotics. Cell Chemical Biology. 2017, 24(2), 171-181.
2. Huang, W., et al. Total synthesis of complex peptidyl nucleoside antibiotics: Asymmetric de novo syntheses of miharamycin B and its biosynthetic precursor. Angewandte Chemie International Edition. 2022, 61(31): e202204907.