Biomedical Engineering Reference
In-Depth Information
NH
2
H
2
N
N
N
NH
2
NH
2
O = S = O
NH
2
O = S = O
COOH
NH
2
Prontosil rubrum
(a)
Sulphanilamide
(b)
PABA
(c)
O
OH
H
NH
C
NH
CH
COOH
N
CH
2
H
H
H
N
(CH
2
)
2
COOH
N
N
H
2
N
H
Pteridine
derivative
Glutamic acid
PABA
Tetrahydrofolic acid
(d)
Figure 1.1
Sulfa drugs and their mode of action. The fi rst sulfa drug to be used medically was the red dye
prontosil rubrum (a). In the early 1930s, experiments illustrated that the administration of this dye to mice
infected with haemolytic streptococci prevented the death of the mice. This drug, although effective
in vivo
,
was devoid of
in vitro
antibacterial activity. It was fi rst used clinically in 1935 under the name Streptozon. It
was subsequently shown that prontosil rubrum was enzymatically reduced by the liver, forming sulfanilamide,
the actual active antimicrobial agent (b). Sulfanilamide induces its effect by acting as an anti-metabolite
with respect to
para
-aminobenzoic acid (PABA) (c). PABA is an essential component of tetrahydrofolic acid
(THF) (d). THF serves as an essential cofactor for several cellular enzymes. Sulfanilamide (at suffi ciently high
concentrations) inhibits manufacture of THF by competing with PABA. This effectively inhibits essential
THF-dependent enzyme reactions within the cell. Unlike humans, who can derive folates from their diets, most
bacteria must synthesize it
de novo,
as they cannot absorb it intact from their surroundings
Although the pharmaceutical potential of these regulatory molecules was generally appreciated,
their widespread medical application was in most cases rendered impractical due to the tiny quan-
tities in which they were naturally produced. The advent of recombinant DNA technology (genetic
engineering) and monoclonal antibody technology (hybridoma technology) overcame many such
diffi culties, and marked the beginning of a new era of the pharmaceutical sciences.
Recombinant DNA technology has had a fourfold positive impact upon the production of
pharmaceutically important proteins:
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