Resistance to Aminoglycosides

The aminoglycoside family of antibiotics includes streptomycin, kanamycin, neomycin, tobramycin, gentamycin and a host of others. Aminoglycosides consist of three (sometimes more) sugar rings, at least one of which (and usually two or three) has amino groups attached. They inhibit protein synthesis by binding to the small subunit of the ribosome (see Ch. 8). Plasmid-borne resistance is due to inactivation of the antibiotics. Several alternatives exist, including modification by phosphorylation of -OH groups, adenylation (i.e. addition of AMP) of -OH groups or acetylation of -NH2 groups. ATP

aminoglycosides Family of antibiotics that inhibit protein synthesis by binding to the small subunit of the ribosome; includes streptomycin, kanamycin, neomycin, tobramycin, gentamycin and many others chloramphenicol Antibiotic that binds to 23S rRNA and inhibits protein synthesis CAT Chloramphenicol acetyl transferase chloramphenicol acetyl transferase (CAT) Enzyme that inactivates chloramphenicol by adding acetyl groups kanamycin Antibiotic of the aminoglycoside family that inhibits protein synthesis neomycin Antibiotic of the aminoglycoside family that inhibits protein synthesis streptomycin Antibiotic of the aminoglycoside family that inhibits protein synthesis

Resistance to Tetracycline 441

FIGURE 16.14 Inactivation of Aminoglycoside Antibiotics

Much like chloramphenicol, members of the aminoglycoside family are inactivated by modification. One member, kanamycin B, can be modified by a variety of covalent modifications, such as phosphorylation, acetylation, or adenylation. A variety of bacterial enzymes make these modifications to prevent kanamycin B from attaching to the small ribosomal subunit.

Aminoglycoside antibiotics are inactivated by addition of phosphate, AMP, or acetyl groups.

is used as a source of phosphate and AMP groups, whereas acetyl-CoA is the acetyl donor (Fig. 16.14).

Modified aminoglycosides no longer inhibit their ribosomal target sites. There are many different aminoglycosides and a correspondingly wide range of modifying enzymes. The npt gene (neomycin phosphotransferase) is the most widely used and provides resistance to both kanamyin and the closely related neomycin. Aminoglyco-sides are made by bacteria of the Streptomyces group, which are mostly found in soil. These organisms need to protect themselves against the antibiotics they produce. Probably, therefore, the aminoglycoside modifying enzymes came originally from the same Streptomyces strains that make these antibiotics.

Amikacin is a more recent derivative of kanamycin A in which the amino group on the middle ring that gets acetylated is blocked with a hydroxybutyrate group. This made amikacin resistant to all modifying enzymes except one obscure N-acetyl trans-ferase. However, evolution moves on and an enzyme that phosphorylates amikacin has already appeared in some bacterial strains!

Tetracycline resistance is due to energy-driven export of the antibiotic.

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