08 September, 2008

British penicillin vs. American penicillin

1) Dr. Chain said:

I had come across this paper early in 1938 and reading it
I immediately became interested. The reason was that,
according to Fleming's description, the mould had strong
bacteriolytic properties against the Staphylococcus
------ when I saw Fleming's paper for the first time
I thought Fleming had discovered a sort of mould lysozyme,
which, in contrast to egg white lysozyme, acted on a wide
range of gram-positive pathogenic bacteria.
I further thought that in all probability the cell wall of all
these pathogenic bacteria whose growth was inhibited by
penicillin contained a common substrate on which the
supposed enzyme acted, and that it would be worth trying
to isolate and characterise the hypothetical common substrate.
For this purpose it would, of course, be necessary to purify
the supposed enzyme, but I did not foresee any undue difficulties
with this task for which I was well prepared from my previous

Shortly after the chemical work had been started at Oxford,
a number of other British research centres( the Imperial College
of Science, Burroughs Wellcome Ltd., Imperial Chemical Industries,
Glaxo), began similar studies.

Simultaneously with the work in England, American chemists began
an intensive study of the structure of penicillin with the aim of quickly
achieving a synthesis. This work was carried out on a very large scale,
with something like 200 academic and industrial research chemists
taking part in the project.

Until May 1944 this work was entirely independent of the British effort,
and we in Britain had no information about the state of the American
investigations, except for a few fragmentary rumours.

In 1943, the British and U.S. Government imposed a ban the publication
of all chemical work on penicillin and simultaneously negotiations were
begun between the two governments for the purpose of finding a suitable
method for a complete exchange of information between the various
groups of workers on both sides of the Atlantic.

These negotiations were protracted, and while they were in progress we
at Oxford got on with our studies and were able to propose the first
complete structural formulae for penicillin in October, 1943.


During the purification studies it became clear that there existed several
penicillins which had very similar biological and chemical properties,
but which differed in their chemical composition. Later work showed that
all penicilins contained common nucleus, but differ in the structure of
their side chains.

So far four different penicillins have been obtained in the form of their
crystalline sodium salts. They are designated in England as penicillins
I,II,III,IV, according to the sequence of their historical discovery;
in America they are termed, F,G,Xand K.


Elementary analysis of the crystalline sodium salts has shown that the
penciliins have the following composition:

Penicillin I (F) C14H20O4N2S
Penicillin II (G) C16H18O4N2S
Penicillin III(X) C16H18O5N2S
Penicillin IV(K) C16H26O4N2S


The final solution of the problem of the structure of penicillin
came from crystallographic X-ray studies. This work, in which
Mrs.D.Crowfoot and her colleague Mrs. Barbara Roger-Low
have played a predominant role, has led to the difinite exclusion
of the thiozolidine-oxazolone structure and to the conclusive
proof of the beta-lactam structure.


Any questions: write to Keiji Hagiwara, MD