Beptember 19, 1956

Dr. J. Leda
Bristel Laboratories
Syracuse 1, N.Y.

Dear Joe:

I suspect you may regard this ae an untranquilising regression, but I had
a thought for a possible approach to a rational chemotherapeutic that my still
be of interest. Lately, I've been following up studhes on penicillin action,
in relation to protoplasts, and more recently to cultivating protoplasts, in
fact the L-form problem. The osmolality of the mdfum is the key to the situation.

Now one of the theoretical difficulties with rational chemotherapy is
finling a reaction which is unique to the paraéite, so the ansagonist does
not either damage the host alao, or is not already reversed by the presence
of the principal metabolite in the host tissues. Penicillin seems to be affecting
such a reaction in wall synthesis: we don't yet know just what it 1s, though the
condensation of sugar residues from uridine-diphospho-conjugated monomers seems
a likely bet. Now there is one metabolite which has been uniqe in bacterial
walls, namely d elic acid, and there are some preliminary indications
(from some work and conversation between Bernie Datis and myself) that auxo trophs
for this compound are defective in wall synthesis, though I've just started to
Play with this, ami don't have it very clear yet at all. If this reasoning és
correct, analogues of DAP should be especially effective chemotherapeutic agentes,
analogous in thelr effect to penicillin.

I haven't seen any mention of trials of such analogues, though the interest
of Work in DAP would seem to make this an unavoidable thought. (The most recent
studies on DAP are in J. Gen Microbiol. 9:394, 12/53; and 14:583, 7/56). I won't
offer any suggestions as to which analogues would be profitable to look for. If
I can coonarst- -- * “sing compounds as "protoplastogens", let me

~rogram. At least the sulfonic analogues