Biosynthetic Pathways of Nucleoside Antibiotics

The biosynthetic pathways of nucleoside antibiotics encompass a diverse array of enzymatic logic that transforms simple sugar and nucleobase precursors into potent inhibitors of bacterial, fungal and protozoal targets. Central to these pathways are biosynthetic gene clusters encoding a suite of enzymes responsible for scaffold assembly, tailoring modifications and self-resistance. Initial steps typically involve sugar activation through phosphorylation or conjugation to phosphoribosyl pyrophosphate, followed by glycosyltransferases or radical S-adenosylmethionine enzymes that forge C– or N–glycosidic linkages. Subsequent oxidative, reductive or methyltransferase reactions introduce deazapurine or aminonucleoside moieties, yielding structural diversity exemplified by puromycin, tubercidin and nikkomycin families. Regulation by pathway-specific transcription factors ensures coordinated expression, while dedicated self-resistance enzymes neutralise active compounds in producer strains. Recent elucidation of high-carbon sugar backbones and 7-deazapurine cores has illuminated the molecular logic of C8 and deazapurine nucleoside formation, opening avenues for combinatorial biosynthesis. These insights underpin global efforts to harness natural biosynthetic machinery and recombinant enzymes for antibiotic discovery, addressing the urgent challenge of multidrug resistance through novel nucleoside scaffolds and engineered analogue production.

Research from Nature Portfolio

Recent studies have illuminated the structures and biosynthetic origins of nucleoside antibiotics through combined microbiological and spectroscopic approaches. Detailed isolation and structural analysis of plicacetin from an endophytic Streptomyces species demonstrated broad-spectrum activity against resistant bacterial and fungal phytopathogens, clarifying its N–glycosidic linkage and sugar-base architecture. In a complementary effort, genomic sequencing and functional characterisation of a Streptomyces albus gene cluster resolved the complete set of enzymes responsible for pseudouridimycin biosynthesis, defining C–glycosidic bond formation and pathway regulation that underpin selective inhibition of bacterial RNA polymerase.

Biosynthetic Pathways of Nucleoside Antibiotics publication trend

The graph below shows the total number of articles in biosynthetic pathways of nucleoside antibiotics across all publications each year (not limited to Nature Index journals).

Technical terms

Biosynthetic gene cluster: Contiguous region of microbial DNA encoding enzymes for natural product assembly.

Radical S-adenosylmethionine (SAM) enzyme: Catalyst that uses SAM to generate radical species for complex bond formations.

C-glycosidic bond: Carbon–carbon linkage between sugar and nucleobase found in C-nucleoside antibiotics.

Deazapurine: Purine derivative lacking a nitrogen atom, forming the core of certain nucleoside antibiotics.

Aminonucleoside: Hybrid molecule combining amino acid and nucleoside moieties, as exemplified by puromycin.

References

1. Purine nucleoside antibiotics: recent synthetic advances harnessing chemistry and biology. Natural Product Reports (2024).
2. Mining Translation Inhibitors by a Unique Peptidyl-Aminonucleoside Synthetase Reveals Cystocin Biosynthesis and Self-Resistance. International Journal of Molecular Sciences (2024).
3. Purification and biological analysis of antimicrobial compound produced by an endophytic Streptomyces sp.. Scientific Reports (2023).
4. Discovery and characterization of the tubercidin biosynthetic pathway from Streptomyces tubercidicus NBRC 13090. Microbial Cell Factories (2018).
5. Characterization of C-nucleoside Antimicrobials from Streptomyces albus DSM 40763: Strepturidin is Pseudouridimycin. Scientific Reports (2019).
6. Construction of an octosyl acid backbone catalyzed by a radical S -adenosylmethionine enzyme and a phosphatase in the biosynthesis of high-carbon sugar nucleoside antibiotics. Chemical Science (2017).