2-Deoxystreptamine-containing aminoglycoside antibiotics: Recent advances in the characterization and manipulation of their biosynthetic pathways

Abstract

The 2-deoxystreptamine-containing aminoglycosides, such as neomycin, kanamycin and gentamicin, are an important class of antibiotics. A detailed understanding of the complete biosynthetic pathway of aminoglycosides and their biosynthetic enzymes will allow us to not only generate more robust antibiotic agents or drugs with other altered biological activities, but also to produce clinically important semi-synthetic antibiotics by direct fermentation. This Highlight focuses on recent advances in the characterization of their biosynthetic enzymes and pathway as well as some chemo-enzymatic and metabolic engineering approaches for the biological production of natural, semi-synthetic, and novel aminoglycosides.

Taxonomy, Physiology, and Natural Products of Actinobacteria

“…For example, streptothricin is found in some 10% of all streptomycetes isolated randomly from soil and streptomycin is found in 1% and actinomycin in 0.1%, while conversely, erythromycin and vancomycin are found in around 10 Ϫ5 soil isolates, and daptomycin is found only at a frequency of around 10 Ϫ7 (412). Major classes of clinical antibiotics produced by actinomycetes are the following: aminoglycosides (neomycin, kanamycin, streptomycin (413)(414)(415), angucyclines (auricin; also, antitumor agents like landomycin and moromycin (416), ansamycins (rifamycin, geldanamycin) (417), anthracyclines (primarily antitumor agents, e.g., daunorubicin) (418,419), ␤-lactams (cephamycins) (420) and also the important ␤-lactamase inhibitor clavulanic acid (421,422), chloramphenicol (423), glutarimides (cycloheximide) (424), glycopeptides (vancomycin, teichoplanin) (425,426), lipopeptides (daptomycin) (427), lantibiotics (mersacidin, actagardine) (272), macrolides (clarythromycin, erythromycin, tylosin, clarithromycin) (428,429), oxazolidinones (cycloserine) (430), streptogramins (streptogramin) (431), and tetracyclines (432). The producing capacity of individual actinomycetes can also vary enormously.…”

Detection and Quantification of Ribosome Inhibition by Aminoglycoside Antibiotics in Living Bacteria Using an Orthogonal Ribosome-Controlled Fluorescent Reporter

“…1 Of the many known classes of ribosome inhibitors, the aminoglycosides (Figure 1a) are perhaps the best-studied with regard to their mechanisms of action 2-4 , drug resistance 2-4 , and biosynthesis. 5-7 Aminoglycosides are a clinically useful class of ribosome inhibitors with broad spectrum activity towards a variety of microbial pathogens. However their widespread clinical use has been hampered by low-level toxicity to human mitochondrial ribosomes.…”

Concentrated biosynthesis of tobramycin by genetically engineered Streptomyces tenebrarius

“…Biosynthetic studies of aminoglycoside antibiotics have progressed remarkably during the past decade (Kudo et al, 2009a;Park et al, 2013). In particular, the advances in biosynthetic enzymes in neomycin and butirosin biosynthetic pathways have greatly facilitated the biochemistry and molecular genetics studies of aminoglycosides in S. tenebrarius (Kudo et al, 2009b).…”