Page 830 - Basic _ Clinical Pharmacology ( PDFDrive )

816 SECTION VIII Chemotherapeutic Drugs

Free tetracyclines are crystalline amphoteric substances of low Tetracyclines are active against many Gram-positive and Gram-
solubility. They are available as hydrochlorides, which are more negative bacteria, including certain anaerobes, rickettsiae, chla-
soluble. Such solutions are acidic and fairly stable. Tetracyclines mydiae, and mycoplasmas. For susceptible organisms, differences
chelate divalent metal ions, which can interfere with their absorp- in clinical efficacy may be attributable to features of absorption,
tion and activity. Tigecycline is a glycylcycline and a semisynthetic distribution, and excretion of individual drugs. Tetracycline-
derivative of minocycline. resistant strains may be susceptible to doxycycline, minocycline,
and tigecycline, all of which are poor substrates for the efflux
Mechanism of Action & Antimicrobial pump, if that is the mechanism of resistance.
Activity

Tetracyclines are broad-spectrum bacteriostatic antibiotics that Resistance
inhibit protein synthesis. Tetracyclines enter microorganisms in Three mechanisms of resistance to tetracycline analogs have
part by passive diffusion and in part by an energy-dependent been described: (1) impaired influx or increased efflux by
process of active transport. Susceptible organisms concentrate an active transport protein pump; (2) ribosome protection
the drug intracellularly. Once inside the cell, tetracyclines bind due to production of proteins that interfere with tetracycline
reversibly to the 30S subunit of the bacterial ribosome, block- binding to the ribosome; and (3) enzymatic inactivation. The
ing the binding of aminoacyl-tRNA to the acceptor site on the most important of these are production of an efflux pump
mRNA-ribosome complex (Figure 44–1). This prevents addition and ribosomal protection. Tet(AE) efflux pump-expressing
of amino acids to the growing peptide. Gram-negative species are resistant to the older tetracyclines,

50S
ribosome

Amino acid
1 C
6
2
M
3
4
2 t6
5 6 1

Charged
tRNA
t5 4 t6
3

mRNA
T
30S

t5 Uncharged tRNA

FIGURE 44–1 Steps in bacterial protein synthesis and targets of several antibiotics. Amino acids are shown as numbered circles. The 70S
ribosomal mRNA complex is shown with its 50S and 30S subunits. In step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor
site on the 70S ribosome. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino
acid 6 (peptide bond formation, step 2). The uncharged tRNA left at the donor site is released (step 3), and the new 6-amino acid chain with its
tRNA shifts to the peptidyl site (translocation, step 4). The antibiotic binding sites are shown schematically as triangles. Chloramphenicol (C) and
macrolides (M) bind to the 50S subunit and block peptide bond formation (step 2). The tetracyclines (T) bind to the 30S subunit and prevent
binding of the incoming charged tRNA unit (step 1).