5. ANTIBIOSIS AND ANTIBIOTICS
331
it is has not been demonstrated that Terramycin-X actually is a precursor of Terramycin. Further, it is known that, if acetate may well
furnish the carbon atoms of the A ring, part of it, the carboxamide chain
and carbon atoms 2,3,4,4a together with 4-amino nitrogen, may be
synthesized from glutamic acid.
Among other tetracycline antibiotics recently studied (317), special
mention should be made of N-methylethyloxytetracycline. This substance, synthesized by a mutant of S. rimosus in the presence of DLethionine (318), offers an example of transethylation similar to that
which yields the 2'-ethoxy analog of griseofulvin (297).
Under suitable conditions, each tetracycline is transformed into the
corresponding epitetracycline, and one obtains a mixture in equilibrium
of the two compounds. Epitetracyclines are the result of racemization at
C-4. They have a reduced antibiotic activity in vitro but not in vivo.
Many derivatives of the tetracyclines have been chemically prepared
(319). The 5a,6-anhydrotetracyclines, obtained by acid degradation, can
be biologically rehydrated (320, 321).
The modes of action of the tetracycline have been recently reviewed
by Snell and Cheng (322). The authors insist on the fact that such antibiotics, with so many functional groups, must have many modes of
action, the relative importance of each one of them being likely to vary
with the biological or biochemical system considered and the experimental conditions chosen.
If the chemical differences existing between the several tetracyclines
explain that they do not act exactly alike, their close similarity of general
structure, on the other hand, accounts for the fact that they have many
effects in common and for the frequent occurrence of cross-resistance.
The often-reported cross-resistance to the tetracyclines and chloramphenicol, despite the lack of any resemblance between these compounds,
linked to the fact that their antibiotic effects are strictly additive, is
interpreted as the consequence of their blocking different biochemical
pathways leading, however, to the biosynthesis of the same final product,
proteins.
At growth-inhibiting concentration, various tetracyclines depress, or
completely abolish, the activity of many enzymatic systems, either in the
cell or isolated, oxygen uptake, and biosynthesis of several substances.
In many instances, the effects of tetracyclines are reversed by divalent
cations (323), which, conversely, were sometimes shown to be indispensable, in suitable concentration, for the manifestation of their activity.
Tetracyclines are in fact known to chelate divalent cations, and it has
been advanced that the biologically active substances might be the metalcomplexed antibiotics rather than the free ones. The main forms of
331
it is has not been demonstrated that Terramycin-X actually is a precursor of Terramycin. Further, it is known that, if acetate may well
furnish the carbon atoms of the A ring, part of it, the carboxamide chain
and carbon atoms 2,3,4,4a together with 4-amino nitrogen, may be
synthesized from glutamic acid.
Among other tetracycline antibiotics recently studied (317), special
mention should be made of N-methylethyloxytetracycline. This substance, synthesized by a mutant of S. rimosus in the presence of DLethionine (318), offers an example of transethylation similar to that
which yields the 2'-ethoxy analog of griseofulvin (297).
Under suitable conditions, each tetracycline is transformed into the
corresponding epitetracycline, and one obtains a mixture in equilibrium
of the two compounds. Epitetracyclines are the result of racemization at
C-4. They have a reduced antibiotic activity in vitro but not in vivo.
Many derivatives of the tetracyclines have been chemically prepared
(319). The 5a,6-anhydrotetracyclines, obtained by acid degradation, can
be biologically rehydrated (320, 321).
The modes of action of the tetracycline have been recently reviewed
by Snell and Cheng (322). The authors insist on the fact that such antibiotics, with so many functional groups, must have many modes of
action, the relative importance of each one of them being likely to vary
with the biological or biochemical system considered and the experimental conditions chosen.
If the chemical differences existing between the several tetracyclines
explain that they do not act exactly alike, their close similarity of general
structure, on the other hand, accounts for the fact that they have many
effects in common and for the frequent occurrence of cross-resistance.
The often-reported cross-resistance to the tetracyclines and chloramphenicol, despite the lack of any resemblance between these compounds,
linked to the fact that their antibiotic effects are strictly additive, is
interpreted as the consequence of their blocking different biochemical
pathways leading, however, to the biosynthesis of the same final product,
proteins.
At growth-inhibiting concentration, various tetracyclines depress, or
completely abolish, the activity of many enzymatic systems, either in the
cell or isolated, oxygen uptake, and biosynthesis of several substances.
In many instances, the effects of tetracyclines are reversed by divalent
cations (323), which, conversely, were sometimes shown to be indispensable, in suitable concentration, for the manifestation of their activity.
Tetracyclines are in fact known to chelate divalent cations, and it has
been advanced that the biologically active substances might be the metalcomplexed antibiotics rather than the free ones. The main forms of