Page 841 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 45 Aminoglycosides & Spectinomycin 827

complex of peptide formation; (2) misreading of mRNA, which
NH 2 causes incorporation of incorrect amino acids into the peptide and
results in a nonfunctional protein; and (3) breakup of polysomes
C NH
CH 3 into nonfunctional monosomes. These activities occur more or
HO NH CH OH
2
NH O CHO O less simultaneously, and the overall effect is irreversible and leads
OH to cell death.
H N C NH O O HO
2
C. Mechanisms of Resistance
HO HO NH HO
Three principal mechanisms of resistance have been established:
CH 3 (1) production of a transferase enzyme that inactivates the amino-
Streptidine Streptose N-methyl-L- glycoside by adenylylation, acetylation, or phosphorylation. This
glucosamine
is the principal type of resistance encountered clinically. (2) There
Streptobiosamine is impaired entry of aminoglycoside into the cell. This may result
from mutation or deletion of a porin protein involved in transport
and maintenance of the electrochemical gradient or from growth
FIGURE 45–1 Structure of streptomycin.

1 2
H 2 C NH 2 NH 2 H 2 C NH 2 NH 2
O O
5 3 2 NH R NH 2
HO 4 I 1 O 4 II 1 HO I O II
3 2 5 6 CH 2 OH CH 2 OH
O O
HO OH HO O 5 NH 2 HO O
4 3 1 III 4 OH III OH
2 3
HO NH 2 HO NH 2
5 Tobramycin
Kanamycin R =H
O OH NH 2
HO
Amikacin R = C CH CH 2 CH 2 NH 2 NH O
I O II NH R
R 1
HC NH R 2 NH 2
O NH 2 HO O O
5 3 2 NH R 3 Plazomicin OH
4 I O II 1 III
O OH
CH 3
O R C CH CH 2 CH 2 NH 2
NH 2 HO O OH HO NH–CH 3
III
2 CH 3
HO NH CH 3
Gentamicin, netilmicin

Ring I Ring II
C4–C5
R 1 R 2 bond R 3
Gentamicin C 1 CH 3 CH 3 Single H
Gentamicin C 2 CH 3 H Single H
Gentamicin C 1a H H Single H
Netilmicin H H Double C 2 H 5

FIGURE 45–2 Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kana-
mycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. Plazomicin’s ring II and III are similar to the other struc-
tures; it shares the same hydroxyl-aminobutyric acid R group as amikacin. Its ring I differs from amikacin in that it is unsaturated. The circled
numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug.
➀, ➁, and ➂, acetyltransferase; ➃, phosphotransferase; ➄, adenylyltransferase. Amikacin is resistant to modification at ➁,➂,➃, and ➄; whereas
plazomicin is resistant to modification at ➀, ➁, ➃, and ➄.