In the next two posts we’ll take a closer look to the oligosaccharides (generally composed from 3 to 10 monosaccharide units). In contrast to disaccharides, we can find lots of interesting active pharmaceutical agents among the oligosaccharides. In the first post we will talk about aminoglycoside type antibiotics, in the second about sugammadex (and a few other molecules).
Aminoglycosides (AG) are a type of antibiotics. These molecules are composed of aminosugars and other monosaccharides (or sugar alcohols) linked by glycosidic bonds. They can be divided into two subclasses: oligosaccharide- and pseudo-oligosaccharide-type aminoglycosides. In the latter we can’t find a ‘real’ glycosidic bond between two carbohydrate units, only between a sugar alcohol (aminocyclitol) and a carbohydrate.
They are concentration-dependent bactericides and inhibit the protein synthesis of the bacteria, by binding to the 30S subunit of the bacterial ribosome.
The first discovered molecule from this subclass (and also the first AG) was streptomycin, isolated from Streptomyces griseus. It is still used nowadays, mainly for the treatment of non-resistant tuberculosis in combination with other drugs.
The most well-known molecule from this subclass is neomycin (1). The carbohydrate units are linked to the 2-deoxystreptamine (an aminocyclitol) core. It is a mixture of three compounds (A, B and C; A is the inactive- degradation product of B and C; B is the C5 (neobiosamine) epimer of C). It is mainly used in topical formulations.
Neomycin B (1)
This subclass contains molecules like kanamycin, tobramycin, gentamicin, netilmicin or amikacin.
Tobramycin (2) is one of the most important molecules from these compounds. It is composed of a disaccharide (nebramin) and a monosaccharide (kanosamin) and lacks the D-ribose unit. It is not absorbed from the gastrointestinal tract, thus for systemic effect it is given only intravenously, however tobramycin is used mainly in topical formulations e.g. in eye-drops (TobrexTM).
One of the newest molecules is plazomicin (ZemdriTM) (3), approved by the FDA in 2018 for multidrug-resistant Enterobacteriaceae1. It consist of three aminosugar subunits with a hydroxy-aminobutyric acid (HABA) substituent at position 1 and a hydroxyethyl substituent at position 6’.
Tobramycin (2) and plazomicin (3)
Beside these types of aminoglycosides there are a few more molecules that can’t be strictly inserted in the subclasses mentioned above. For example, apramycin has a condensated carbohydrate unit in its structure (it is used only in agriculture and veterinary medicine). Another example is spectinomycin, what is any aminocyclitol derivative (used mainly in penicillin resistant cases).
The most common side effects of AGs are oto- and nephrotoxicity. The former one can be permanent and dose independent3.
All in all, AGs are a big class of antibiotics with broad antimicrobial spectra, but they are used mainly in topical formulations because of their side-effects. For systemic use they are only second-line drugs, used only when the first-line drugs (e.g. cephalosporins, carbapenems, fluoroquinolons) can’t be applied (mainly because of bacterial resistance).
In the next post the introduction of oligosaccharide type drugs will be continued by the first cyclodextrin with known pharmacological effect –Sugammadex– and other cyclodextrins as APIs.
1 Shaeer, K.M.; Zmarlicka, M.T.; Chahine, E.B.; Piccicacco, N. and Cho, J.C.Plazomicin: A Next-Generation Aminoglycoside, Pharmacotherapy, 2019, 39(1):77-93
2 Black, F.O.; Pesznecker, S and Stallings, V. Permanent gentamicin vestibulotoxicity, Otol neurotol, 2004, 25(4):559-569