Biomedical Engineering Reference
In-Depth Information
25.4
ANTIBIOTICS AFFECTING NUCLEIC ACID SYNTHESIS
25.4.1 A
CTINOMYCIN
AND
A
NTHRACYCLINES
One of the i rst antibiotics discovered by Waksman was actinomycin, isolated from
Streptomyces
antibioticus
(Waksman and Woodruff, 1940). Subsequently several related actinomycins were
described, and they differed by one or two amino acids in the peptide part. Their structure was elu-
cidated by Brockmann et al. in Germany and A.W. Johnson in England. They have a phenoxazone
chromophore, to which are linked two identical peptidyl-lactone rings. The product that is usually
used in the clinic is actinomycin D = dactinomycin. It is used for treatment of tumors.
The i rst anthracycline to be described was rhodomycin (Brockmann and Bauer, 1950). The
toxicity of this product was too high even for the treatment of cancer. The i rst clinically useful
product was daunorubicin. It was discovered independently in 1963 at Rhone-Poulenc in France and
at Farmitalia. In France it was isolated from
Streptomyces coeruleorubidus
and called rubidomy-
cin and in Italy from
S. peucetius
and called daunomycin. Daunorubicin is a combination of both
names. Doxorubicin (also called adriamycin) was obtained in 1969 from
S. peucetius
strain cae-
sius. Both have an anthraquinone chromophore to which the amino sugar daunosamine is attached
(Figure 25.7).
CH
3
CH
3
O
OH
O
O
CO
CH
2
R
OH
N
NH
2
O
O
H
CO
CO
CH
3
O
OH
Y
Y
H
Pro
Thr
Pro
Sarc
MeVal
Thr
O
H
Sarc
MeVal
O
O
CH
3
H
H
HO
NH
2
H
Actinomycin
D = Dactinomycin
Daunorubicin
Adriamycin
Y =
D
-Valine
R = H
R = OH
Actinomycin C
Y =
D
-Alloleucine
FIGURE 25.7
Anticancer antibiotics.
25.4.2 A
NTIBIOTICS
THAT
I
NHIBIT
RNA P
OLYMERASE
R i fa myc i n i s a n a n t ib io t ic t h a t wa s d i s c ove r e d a t L e p e t it i n It a ly i n 19 57 i n a s t r a i n of
Streptomyces
,
now reclassii ed as
Nocardia mediterranii
. In 1963, it was discovered that the most impor-
tant component, rifamycin B, was transformed by oxygenation of the aqueous solution into a
more active product, rifamycin O, which on mild reduction gave rifamycin SV (Sensi, Furesz).
Rifamycin SV reacts with formaldehyde to form formyl rifamycin, which on condensation with
N
-amino-
N
-methylpiperazine yields rifampicin. The determination of the structure was per-
formed by Oppolzer and Prelog (1964). Later, rifaximin was introduced whose spectrum is an
analogue of rifampicin.
Rifamycin is very active against Gram-positive bacteria and some Gram-negative ones and
against
Mycobacterium tuberculosis
. Rifampicin gives a better, more regular absorption and is an
excellent drug in the treatment of tuberculosis and leprosy. Rifaximin is used for gastrointestinal
infections (Figure 25.8).
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