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

1464
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
H 2 N
H 2 N
4 1
H 2 N
SO 2 NH 2
SULFANILAMIDE
SULFAMETHOXAZOLE
SO 2 NH
SULFACETAMIDE
Although sulfonamides were used successfully
for the management of meningococcal infections for
many years, most isolates of Neisseria meningitidis of
serogroups B and C in the U.S. and group A isolates
from other countries are now resistant. A similar situation
prevails with respect to Shigella. Strains of E. coli
isolated from patients with urinary tract infections
(community acquired) often are resistant to sulfonamides,
which are no longer the therapy of choice for
such infections.
Mechanism of Action. Sulfonamides are competitive
inhibitors of dihydropteroate synthase, the bacterial
enzyme responsible for the incorporation of PABA into
dihydropteroic acid, the immediate precursor of folic
acid (Figure 52–2). Thus, these structural analogs of
para-aminobenzoic acid (PABA) prevent normal bacterial
use of PABA for the synthesis of folic acid (pteroylglutamic
acid). Sensitive microorganisms are those that
must synthesize their own folic acid; bacteria that can
use preformed folate are not affected. Bacteriostasis
induced by sulfonamides is counteracted by PABA
competitively. Mammalian cells require preformed
folic acid, cannot synthesize it, and are insensitive to
drugs acting by this mechanism. Thus, mammalian
cells are comparable to sulfonamide-insensitive bacteria
that use preformed folate.
Synergists of Sulfonamides. One of the most active
agents that exerts a synergistic effect when used with a
sulfonamide is trimethoprim (Bushby and Hitchings,
O
C
SULFADIAZINE
O
N
CID
CH 3 H 3 C CH 3
SULFISOXAZOLE
CH 3
H 2 N
SO 2 NH
SO 2 NH H 2 N SO 2 NH
N
O
H 2 N
COOH
N
N
PARA-AMINOBENZOIC ACID
Figure 52–1. Structural formulas of selected sulfonamides and para-aminobenzoic acid. The N of the para-NH 2
group is designated
as N4; that of the amide NH 2
, as N1.
1968). This compound is a potent and selective competitive
inhibitor of microbial dihydrofolate reductase,
the enzyme that reduces dihydrofolate to tetrahydrofolate.
It is this reduced form of folic acid that is required
for one-carbon transfer reactions. The simultaneous
administration of a sulfonamide and trimethoprim thus
introduces sequential blocks in the pathway by which
microorganisms synthesize tetrahydrofolate from precursor
molecules (Figure 52–2). The expectation that
Pteridine + PABA
sulfonamides
Dihydropteroic acid
glutamate
Dihydrofolic acid
NADPH
trimethoprim
NADP
Tetrahydrofolic acid
Figure 52–2. Steps in folate metabolism blocked by sulfonamides
and trimethoprim.