Biosynthesis and biotechnological engineering of aminoglycosides: Pathways, enzymes, and industrial prospects

Aminoglycosides (AGs) are a broad class of antibiotics widely used in medicine since the 1950s. Challenges remain in creating highly stereoselective modifications with traditional chemical methods. Biosynthesis, which involves enzymatic formation of AGs via genetically encoded pathways in microbes, offers a more efficient, selective, and eco-friendly alternative. The biosynthetic routes of key AGs such as neomycin (NEO), kanamycin (KAN), gentamicin (GEN), tobramycin (TOB), apramycin (APR), and sisomicin (SIS) have been mapped out, involving enzymatic steps like aminocyclitol core formation, glycosylation, and tailoring modifications. Due to rising concerns over bacterial resistance, nephrotoxicity, and ototoxicity, biotechnology approaches that modify enzymes or reprogram pathways provide promising strategies for developing next-generation AGs. This review summarizes current advances in AG biosynthesis, emphasizes enzyme-based methods, and outlines future directions for industrial production and the rational design of AG derivatives via biotechnology.