LiEMORANDU.A

BRISTOL LABORATORIES

UNIT OF BRISTOL-MYERS COMPANY

 

 

J. Lederberg March 21, 1955
FROM _ ee DATE__._.

J, Lein New Antibiotics Screening Program -
TO SUBJECT._Consultantship Arrangement =.
CC.

Hi Joe,

Thanks very much for sending me the account of your general screening progran. I
can see I have quite a job cut out ahead of me if you really exvect me to bring up
anything that might lead to any substantial improvement. I just wanted to gay now
that I have listened to your account once and before I go into very much detail I
would like a few more days in which to mull things over as I'm sure you'd like to
have more than an off-the-cuff response. I might say that my general reaction was
extremely favorable, I might say almost enthusiastic. In fact, I would almoet be
led to think that the one outfit, which apparently has thought to vrovide iteelf
with outside genetic consultation, is perhaps already so well oriented with the
desirability of it and with the fundamental aporoachers that might be added there that
it may not need it. I'll do my best to earn my way with you, Joe, but I, frankly,
con't exvect that I will be able to add a great deal to what you have already laid
out. If I can think of particular things or generalities I will make notes on them
and record them as they go along and I undoubtedly will have somewhat more detailed
comments on this last, particular record,

I wae quite struck however curing listening to your last record that oractically
every comment that I began to formate in my own mind as you went along merely
anticipated what you were going to go into yourself. I do agree that the type of
-poroach which Kilner firet made use of -- I might say I was a little esurorised that
he had the initiative to go into it as far as he did'and then disappointed that he
didn't carry it a little bit further, but it would seem to me that that would indeed
ve a highly promising type of affair but the important point will be to try to
eatablish methods that are as efficient as possible for the detection of the widest
variety of the accumulating tyve of variant.

I approach this whole question of antibiotic screening with the question in the back
of my mind, "just what are antibiotics?" and I was very pleased that you yourself
vrourht that up. I can see that you have been giving, of course, your concentrated
attention to this whole field for a number of years whereas my interest in it so far
has been highly casual and it may take quite a bit of time before I can catch up
with you in any particular area, not to mention the whole concent of what you are
doing. Your report did give me a very clear idea of what your general approach is
and I don't think there will be any general statements that will need to be amplified
although I may want to go into some of the very particular details.

One comment about this technique of going about things, you will vrobably set from me
a combination of written and spoken mterial. ‘when there is something that needs to
be outlined, the structure of which has to be seen at once, it is, of course, much
better on naver than it is on a dictation. On the other hand, I do think that using
the records crovides « much more intimate touch and enables one to digress somewhat
on things that are too fleeting sometimes to put down on nacer and I think that with
To: J. Llein March 21, 1955 New Antibiotics Screening «
Coneultentshiv Arrangement

m little oractice we ~y find that 2 combinaticn of the spoken and the written word
will be much more effective.

Technically, your record is, I think, ocuite satisfactory althouzh I think it could
be imoroved slientiy if you would apeak more loudly, or rather sveak more closely

to the microvhone itself. If you make some records of your own you might commare
them with the one that I have here. Otherwise there may be something defective
with your machine because I know it is canable of producing a higher fidelity than
tne record that I have received, although it wae quite adecuate. The recording
that I am sending you now is not, to use that unhavpy metarhore, up-to-scratch itself
because we have been using in the decartment resurfaced records, that is, once the
records have been used once they can de sent to the service outlet and have a new
surface out on but these records are often not quite as smooth as the new ones. I
think you'll have no trouble whatever in getting my langusze here however. I think
then that with the simple comment that off~hand I did not find very much that one
could obviously improve upon and that I want to let the matter run around in my head
for awhile, so to aneak, that I won't say anymore at the cresent time so this is
essentially an acknowledgement of your first assignment and I want to tell you that
I am giving it ae much consideration as I have time for. [t hanoens to be a rather
busy couple of weeks because I have a meeting comine up in Washington which

however will be over with by the end of the week and I will be able to rive closer
immediate attention to this stuff.

There is one carticular thing that I would like to ask you sbout on the experimental
Drogram and that is that you mentioned that you sre using Actinomyces which have no
evident activity to start with. Since there are vcrobably two functions which one
hae to consider for the efficiency of antibiotic production by an Actinomycete I
wonder if this is necessarily the only choice that might be made. The two functions
that I have in minc are first the metabolic canability of accumulating 2 given
metabolite which, for the purposes of agreevent with you on the general function of
antibtotics is what I will consider a petential antibiotic to be. The other ia the
ability to excrete this into the medium in very large amounts, And it seene to me
conceivable that the processes of selection by means of which the most efficient
croducers of antiblotics have been obtained might have not only some snecial
attribute with regard to that srecific antibiotic but Sleo the more generalized one
of hich incidences of metabolic metabolite accumulation and excretion into the
medium. Now to cut it in other temra, the point of view of tne artificial selection
which one ugea on Streptomyces strains, some of the so-to-espesk adaptation of the
strain miznt be highly svseific and directed toward that particular antibiotic and

in fact might be maladacted with reavect ta any cther metabolite. On the other hand,
some of that so-toesvenk adaptation might be more generalized. what I mean in more
concrete terms ie that conceivably or, at least as an alternative possibility, one
might for such a screening program use not an organiem with an indifferent caveacity
to nroduce sny antibiotic but one which has already been selected for a moderate-to-
high cavacity to croduce one acecific antibiotic already. Then by using a test
organism which waa resistant to that first antidictic, one would be in «an sdvantageous
orocedure for selecting alternatives. This may have © ueever meaning than the one

I nave alreacy oresented. There hec been, for example, considerable attention given
to the vossibility of finding derivative streptomycine which would not show such strons
Tos J. Lein March 21, 1955 Rew antibiotics Screening -
Coneultantshio Arrangement

croge-reeiatance to strectomycin itself and you face the same situation as between
tetracycline and ita chlorinatedand hydroxylated derivatives. And I have wondered
it it would not be a feasible approach to look for the specific modification, the
evecific biological modification of there metabolites os a starting point for new
antiblotics, namely, by using good high-produeing straing for a given antibiotic in
attemting to croduce derivatives from it whicn would be effective against bacterial
mutants which were reaistent against the originel. dJuet to be sure that I have made
myself clear, what I would mean is thet one would take the highest sroducing strein
now eveilable or perhape nearly the highest, say for satrestomycin, and look for
variante of this strain which will have some activity aeainst some of e number of
atrentonycin-resistant mutants, let us say of B. subtilis or of anything eles. There
is the possibility that one would be getting = specific dirsetion of selection for
antiblotics by finding apecific metabolic modifications of streptomycin which would
in some way be able to surmount the barrier of genetic resistance. By itself, this
would of course by a very considerable contribution.

yell, you will hear directly from me again as soon as I have had some better
opportunity to assimilate what I have hera. I did want to give tnat varticular
suggestion just ae a teat sample to see if thet is the kind of thing that you sre
looking for because [ am still go struck by the adequacy of ths anprosch that you
have already given that I hardly know in what way I will be able to contribute.
Well, so long now.

Josh
TLimjl