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CASE FILES: BIOCHEMISTRY
growth (see Figure 9-1).
Aminoglycosides
interfere with binding of fMet-
tRNA to the ribosome, thereby preventing correct initiation of protein synthe-
sis and partially freezing the complex.
Puromycin,
on the other hand, causes
premature termination of protein synthesis because it resembles tyrosyl-tRNA.
It can bind to the
A
-site on the ribosome, and the peptidyl transferase will form
a peptide bond between the growing peptide and puromycin. However, since
there is no anticodon to bind to the mRNA, the peptidyl-puromycin is released
from the ribosome following formation of the peptide bond, thus stopping the
synthesis.
Tetracyclines
inhibit protein synthesis in bacteria by blocking the
A-site on the ribosome and inhibiting binding of aminoacyl tRNAs.
Macrolides
(see below) bind to the 50S subunit near the P-site to cause
conformational changes and inhibit translocation of the peptidyl tRNA
from the A-site to the P-site.
Lincosamides
bind near the P-site and interfere
with binding of the aminoacyl end of the AA-tRNA. They occupy the site or
change the ribosomal conformation such that it destabilizes the ribosomes and
the growing chains fall off the mRNA.
Chloramphenicol
inhibits protein syn-
thesis by bacterial ribosomes by blocking peptidyl transfer. It inhibits peptide
bond formation between AA-tRNA and the growing chain on the
P
-site by
inhibiting peptidyl transferase.
Neomycin, kanamycin,
and
gentamicin
inter-
fere with the decoding site in the vicinity of nucleotide 1400 in 16S rRNA of
30S subunit. This region interacts with the wobble base in the anticodon of
tRNA and blocks self-splicing of group I introns.
Streptomycin,
a basic trisac-
charide, causes misreading of the genetic code in bacteria at relatively low
concentrations but can inhibit initiation at higher concentrations.
Macrolide antibiotics constitute a group of 12- to 16-membered lactone rings
substituted with one or more sugar residues, some of which may be amino sug-
ars. Macrolides such as erythromycin (Figure 9-2) are generally bacteriostatic,
although some of these drugs are bactericidal only at very high concentrations.
Gram-positive bacteria accumulate approximately 100 times more erythromycin
than do gram-negative microorganisms. Cells are considerably more permeable
to the nonionized form of the drug, which explains increased antimicrobial activ-
ity observed at alkaline pH. The newer macrolides have structural modifications,
such as methylation of the nitrogen atom in the lactone ring, that improve acid
stability and tissue penetration of these agents. Macrolides act by binding
reversibly to the ribosomal subunits of sensitive microorganisms and thereby
inhibiting protein synthesis. Resistance to macrolides in clinical isolates is most
frequently a result of posttranscriptional methylation of an adenine residue of
23S ribosomal RNA, which leads to coresistance to macrolides. Other mecha-
nisms of resistance involving cell impermeability or drug inactivation have also
been detected. It is believed that erythromycin does not inhibit peptide bond for-
mation directly but rather inhibits the translocation step wherein a newly syn-
thesized peptidyl tRNA molecule moves from the acceptor site on the ribosome
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