5. ANTIBIOSIS AND ANTIBIOTICS
275
of antibiotics of this family have confirmed the suggestion (76, 77a,b).
A typical aliphatic tripeptide (XXXVIIa) was isolated from the mycelium of Penicillium chrysogenum (78a). Its cyclization through dehydrogenation would produce a particular member of the penicillin family
(XXXVIIb), which is in fact synthesized in the cultures of Cephalosporium salmosynnematum (37), of some strains of Paecilomyces persicinus (78b) and of other fungi (78c), and variously known as cephalosporin N, synnematin B, or salmotin. Although this antibiotic has never
been found as such in cultures of Penicillium spp. or of Aspergillus flavus,
the producers of the other natural penicillins, it is nevertheless believed
to be their common precursor from which they would be derived by
transamidation (79).
It is well known that addition to the culture medium of a suitable
precursor may favor the selective production of a given penicillin or even
result in the elaboration of a new semisynthetic penicillin. It was even
suggested that the biological significance of penicillin formation was that
of a detoxication mechanism (80). New semisynthetic penicillins can
also be prepared by chemical means from a natural one. This involves a
reaction with either a functional group of the side chain from a natural
penicillin, for instance hydroxybenzylpenicillin, or the amino group of
6-aminopenicillanic acid (81-84b). This substance* can now be obtained
either directly from a suitable Penicillium culture (85a,b, 86a) or,
through the action of an amidase, from Phenoxymethylpenicillin or
benzylpenicillin (85b-86f).
The characteristic side chains of the natural
penicillins and of a few of the innumerable semisynthetic ones are shown
in Table I. Total or partial synthesis of the penicillins has also been
achieved (86g).
The penicillins have a very wide spectrum of activity, provided that
a sufficient concentration of the antibiotic is used. But each one of them
has its own specificity of action, quantitatively different from that of the
others (87-92d).
They also differ as to their sensitivity to acids (93)
and as to their capacity of acting either as substrate or inducer of the
penicillinases (94, 95, 96a-g). However, they all appear to act according
* It has been recently reported that alkaline hydrolysis of penicillins yields a
small amount of 6-aminopenicillanic acid [F. R. Batchelor and J. Cameron-Wood,
Nature 195, 1000 (1962)]. All preparations of this compound contain penicillin-like
substances (factors 1, 2, and 3) that are sensitive to penicillinase. Factor 2 is biologically inert, but factor 1 is probably responsible for most of the activity against
gram-positive organisms, but not against gram-negative ones, formerly attributed to
6-aminopenicillanic acid itself [F. R. Batchelor, M. Cole, D. Gazzard, and G. N.
Rolinson, Nature 195, 954-955 (1962)]. The penicillin-like substances are dialyzable
and therefore distinct from the poly-6-aminopenicillanic acid described by Ν. H.
Grant, D. E. Clark, and Η. E. Alburn [/. Am. Chem. Soc. 84, 876-877 (1962)].
275
of antibiotics of this family have confirmed the suggestion (76, 77a,b).
A typical aliphatic tripeptide (XXXVIIa) was isolated from the mycelium of Penicillium chrysogenum (78a). Its cyclization through dehydrogenation would produce a particular member of the penicillin family
(XXXVIIb), which is in fact synthesized in the cultures of Cephalosporium salmosynnematum (37), of some strains of Paecilomyces persicinus (78b) and of other fungi (78c), and variously known as cephalosporin N, synnematin B, or salmotin. Although this antibiotic has never
been found as such in cultures of Penicillium spp. or of Aspergillus flavus,
the producers of the other natural penicillins, it is nevertheless believed
to be their common precursor from which they would be derived by
transamidation (79).
It is well known that addition to the culture medium of a suitable
precursor may favor the selective production of a given penicillin or even
result in the elaboration of a new semisynthetic penicillin. It was even
suggested that the biological significance of penicillin formation was that
of a detoxication mechanism (80). New semisynthetic penicillins can
also be prepared by chemical means from a natural one. This involves a
reaction with either a functional group of the side chain from a natural
penicillin, for instance hydroxybenzylpenicillin, or the amino group of
6-aminopenicillanic acid (81-84b). This substance* can now be obtained
either directly from a suitable Penicillium culture (85a,b, 86a) or,
through the action of an amidase, from Phenoxymethylpenicillin or
benzylpenicillin (85b-86f).
The characteristic side chains of the natural
penicillins and of a few of the innumerable semisynthetic ones are shown
in Table I. Total or partial synthesis of the penicillins has also been
achieved (86g).
The penicillins have a very wide spectrum of activity, provided that
a sufficient concentration of the antibiotic is used. But each one of them
has its own specificity of action, quantitatively different from that of the
others (87-92d).
They also differ as to their sensitivity to acids (93)
and as to their capacity of acting either as substrate or inducer of the
penicillinases (94, 95, 96a-g). However, they all appear to act according
* It has been recently reported that alkaline hydrolysis of penicillins yields a
small amount of 6-aminopenicillanic acid [F. R. Batchelor and J. Cameron-Wood,
Nature 195, 1000 (1962)]. All preparations of this compound contain penicillin-like
substances (factors 1, 2, and 3) that are sensitive to penicillinase. Factor 2 is biologically inert, but factor 1 is probably responsible for most of the activity against
gram-positive organisms, but not against gram-negative ones, formerly attributed to
6-aminopenicillanic acid itself [F. R. Batchelor, M. Cole, D. Gazzard, and G. N.
Rolinson, Nature 195, 954-955 (1962)]. The penicillin-like substances are dialyzable
and therefore distinct from the poly-6-aminopenicillanic acid described by Ν. H.
Grant, D. E. Clark, and Η. E. Alburn [/. Am. Chem. Soc. 84, 876-877 (1962)].