Aminoglycosides

Streptomycin (STR, Fig. 10; 1a), kanamycin (KM, Fig. 10; 1b-d), and amikacin (AK, Fig. 10; 1e) (Fig. 8) comprise the main aminoglycosides used in TB chemotherapy. As discussed in Sect. 1.2, the aminoglycosides are still widely used in modern TB drug regimens although mainly as second-line agents. The general structure of the aminoglycosides is characterized by an aminocyclitol ring connected to one or more amino sugars by a glycosidic linkage. The second generation aminoglycosides KM and AK were largely developed to circumvent resistance mechanisms in other bacteria, not specifically for MTb; hence, their SAR will not be discussed.

This class of antitubercular compounds primarily acts by binding to the 16S rRNA of the bacterial 30S ribosomal subunit, which interferes with protein synthesis and ultimately leads to cell death [125]. As such, resistance mechanisms observed in clinical isolates have principally been the acquisitions of mutations in the 16S rRNA gene (rrs) and in genes that encode for proteins that interact with the 16S rRNA in the region where the drug binds [125-129]. Alternative resistance mechanisms that have been reported include drug efflux and inactivation by aminoglycoside-modifying enzymes, but there is little evidence to suggest these are clinically relevant [130-132]. Common adverse effects associated with aminoglycoside therapy include nephro- and ototoxicity [133, 134].

Streptomycin

Fig. 10 Aminoglycoside antibiotics

Streptomycin

R2 OH HO O

R2 OH HO O

Kanamycin 1b R, = NH2, R2 = OH 1c R, = NH2, R2 = NH2 1d R, = OH, R2 = NH2

NH2 OH

,nh2

Kanamycin 1b R, = NH2, R2 = OH 1c R, = NH2, R2 = NH2 1d R, = OH, R2 = NH2

O OH

Amikacin 1e

Fig. 10 Aminoglycoside antibiotics

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