section 16.2
Biosynthesis of Peptidoglycans
327
donor
G — M
[
LA Ia
I
D G Iu
N H
H N — C H — (C H ) — C H
I
C O O H
C O O H
D A Ia
C O
C O + H J M — C H — (C H ,),— C H
.
*
"
(
N H
D A Ia
(D A Ia
acceptor
released
I
D G Iu
LA Ia
I
-G — M— G — M-
H
H
h
N—C—
V
\
;— 9
\
/CH,
(A) I
® > < CH3
;-r—N.
/
CH=
H
COOH
6
-Aminopenicillanic acid
H
H
H
® —N—C— C/ S ^ C < ”
I ® I
©
I
H
0
o^ c—
n^
C>
h, - 0- <
°
I
1
^CH,
COOH
7
-Aminocephalosporanic acid
FIGURE 16-20
Cross-link formation by a transpeptidase reaction of the disaccharide
pentapeptide (donor) and a disaccharide tetrapeptide (acceptor) which
forms part of existing murein. The terminal D-Ala of the pentapeptide
is released during this process and the s-amino group of donor
dipeptidylaminopeptidase remains free. The free amino group can be
labeled by dansylation. The box indicates the dominant bisdisaccharide
tetratetra compound (Tet-Tet). M,N-acetylmuramic acid;
G,N-acetylglucosamine. [Reproduced with permission from N. Nanninga:
Cell division and peptidoglycan assembly in
E sch erich ia coli. M ol.
M icrobiol.
5:792 (1991).]
chains on linear proteoglycans that have already been at-
tached to the cell wall. Since the degree of cross-linking
is directly related to the extent to which this secondary
transpeptidation occurs, CPases may also influence the
extent of cross-linking in this manner.
Penicillins and Cephalosporins
The penicillins contain a bicyclic ring system formed by
fusion of a thiazolidone ring with a /1-lactam ring. Substi-
tution in this ring system produces 6-aminopenicillanic
acid, the parent compound for the penicillins (Fig-
ure 16-21). The cephalosporins, discovered in 1948,
are derivatives of 7-aminocephalosporanic acid (Figure
FIGURE 16-21
Structures of parent compounds for the /i-lactam antibiotics. In the first
structure, if R = H, the compound is
6
-aminopenicillanic acid; in the
penicillin antibiotics, R is an acyl group. In the second structure, if
Ri = H, the compound is 7-aminocephalosporanic acid; in the
cephalosporins, Ri is an acyl group. The group in parentheses attached to
ring C may also vary in the cephalosporins. Ring A is a ,
8
-lactam ring;
ring B is a thiazolidine ring; ring C is a dihydrothiazine ring. The dotted
line through the C-N bond in the /
8
-lactam rings indicates the site at which
penicillins and cephalosporins are inactivated by /
1
-lactamase
(penicillinase), a bacterial enzyme.
16-21), which contains a dihydrothiazine-/3-lactam ring
system closely related to the penicillin ring system. Bacte-
ricidal activity of the penicillins and the cephalosporins is
based primarily on their ability to inhibit bacterial cell wall
synthesis.
Penicillins inhibit the transpeptidation reaction that
cross-links linear peptidoglycans to form the saccular cell
wall. Eubacteria have three to eight distinct
penicillin-
binding proteins
(PBPs) in the cytoplasmic cell mem-
brane (the inner cell membrane in gram-negative bac-
teria). All are integral membrane proteins, requiring
detergents for solubilization, and have molecular weights
ranging from 40,000 to 140,000. There are approximately
1000 to 10,000 molecules of PBP per cell (about 1% of
the cell membrane protein). Individual PBPs make up
1-90% of the total penicillin-binding activity of a par-
ticular species. The PBPs involved in lateral wall syn-
thesis and those (including PBP 3) involved in septum
formation during cell division are different. The /3-lactam
mecillinam is a specific inhibitor of lateral wall elongation,
while piperacillin is
a specific
inhibitor of septum
formation.
PBPs can be classified into two groups, large and
small PBPs. Large PBPs, i.e., those having molecular
weights ranging from about 60,000 to
140,000, are
sensitive to both penicillins and cephalosporins. They
are quantitatively minor components of the cell membrane
