DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1480
A
Gram positive
Gram negative
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
B
Teichoic
acid
Peptidoglycan
layers
(murein)
Peptidoglycan
layer
Periplasmic
space
NAG NAM
linker
-Lactamase
Cell wall
Lipoprotein
Peptidoglycan
layers
Plasma membrane
Specific
channel
protein
Penicillin binding protein (PBP)
Glycopeptide polymer outside the cell
GT
NAG NAM NAG NAM NAG NAM
TP
NAG
NAM NAG NAM NAG NAM
Porin channel
O Polysaccharide
Lipid A
Proteins
L-Alanine
D-Glutamate
L-Lysine
Glycine
D-Alanine
NAM=N-Acetyl-muramic acid
NAG=N-Acetyl-glucosamine
TP=transpeptidase
GT=glucosyltransferase
=(gly) 5 bridge
Lipopolysaccharide
(LPS)
Outer
membrane
Periplasmic
space
-Lactamase
Phospholipid
lipid II
PBP2
Membrane
Cytosol
Figure 53–3. A. Comparison of the structure and composition of gram-positive and gram-negative cell walls. (Fig. 4-11, pg 83 from
Microbiology: An Introduction, 3rd ed. By Gerard J. Tortora, Berdell R. Funke, and Christine L. Case. Copyright © 1989, 1986, 1982
by the Benjamin/Cummings Company, Inc. Reprinted by permission of Pearson Education, Inc.) B. Schematic of Penicillin Binding
Protein 2(PBP2) from S. aureus. PBP2 has two enzymatic activities that are crucial to synthesis of the peptidoglycan layers of bacterial
cell walls: a transpeptidase that crosslinks amino acid side chains, and a glycosyltransferase that links subunits of the glycopeptide
polymer (see Figure 53–2). The transpeptidase and glycosyltransferase domains are separated by a linker region. The
glycosyltransferase is thought to be partially embedded in the membrane.
β-lactam antibiotic molecules can penetrate easily to the outer layer
of the cytoplasmic membrane and the PBPs, where the final stages
of the synthesis of the peptidoglycan take place. The situation is different
with gram-negative bacteria. Their surface structure is more
complex, and their inner membrane, which is analogous to the cytoplasmic
membrane of gram-positive bacteria, is covered by the outer
membrane, lipopolysaccharide, and capsule (Figure 53–3). The outer
membrane functions as an impenetrable barrier for some antibiotics
(Nakae, 1986). Some small hydrophilic antibiotics, however, diffuse
through aqueous channels in the outer membrane that are formed by
proteins called porins. Broader-spectrum penicillins, such as ampicillin
and amoxicillin, and most of the cephalosporins diffuse through the
pores in the E. coli outer membrane significantly more rapidly than
can penicillin G. The number and size of pores in the outer membrane
vary among different gram-negative bacteria. An extreme
example is P. aeruginosa, which is intrinsically resistant to a wide
variety of antibiotics because it lacks the classical high-permeability
porins (Nikaido, 1994). Active efflux pumps serve as another mechanism
of resistance, removing the antibiotic from its site of action
before it can act (Nikaido, 1998) (Figure 53–5). This is an important
mechanism of β-lactam resistance in P. aeruginosa, E. coli, and
Neisseria gonorrhoeae.