Joshua Lederberg
Hadisea, Viseonsin
Jane 12, 1956

Fy. Jeserh Leta
Bristel Laberateries Ine.
Syrecuse, Yew York

bear Joe:

Taie le just by way of a brief reply te some of your notes dated June
Sth. Unfortuantely the sechanism of action of BMD sgar hae been «a prefonad ayetary
to us too, in spite of the very extensive 290 wea anke of this mediwe. I thersfere
om net sure how I would be able to interpret eny cartieular ontterne of reavense
wat if voeeibdle I venld like to have a chamee to see thes if we mansce a sumer
visit. It seens to me guite poeelble that you are rumning inte iahibitions of acid
formtion and that these could te fairly almply confirmed ty teete in email
volumes of liquid media with stendard indlestors.

I hed not until recently aporeciated that Jardol really hed aay setentific
Basia. If i am gving to de some casual exveriaentation wth “nlerisin, I wonder if
I should net also include some of this fabulous sedium isuryl sarcotinate, and if
you could poseibly furniah me with a sample I will be hescy to de eo.

i am very much interseted in your rewarce on the inhibition of netility
vy Seorin and will try sometine to confirm thie particular experiment. It would,
for exanp)s, de a matter of very considerable interest to me, aside from the
mechanisn of action of the drug, to be able te obtein mutants which are realetast
te thie agent. I am somewhat discouraged however by the very high levels thet weuld
have to be ewployed. The troubles that you mentioned with sotility avar have
setasionelly Aagrened to us, even with the unaltered medium. I think that if 1+
were roseible for you te arrange te ade your supplement te ateriis tubes and thes
mix in freehly autoclaved sotility agar and thea wait 26 to 46 Nourse for the tudes
te dry sroperly that you might have lees diffieulty. If you think the trouble ie
deeoer than thie and could send me 4 sample ef a particularly troublesese broth,

i would be very hapoy to look at it, and see how thie compares with our own
exveriences. I reesll, for example, that we never were able tc inccrvorats mt-rials
Vike nethoes] Late euch median beeause there were acecifie orecivitation effecte,

The sain peint that I wanted to clarify in this resvenes, Joe, hae to do
with why I think renide might be synergistic with veniclllia. The reeson that 1!
wrought ‘eaide up at 21] wee the hint thet it might fuaction in » relative sense as
» competitive inhibiter of cenicillinase. If thie is the enee, then Tenide tizht
awake pemielliia mere affective in chenotheracy of infeetions by nenleillinase-crodueing,
resistant organiems. fhe ishibition of cenieillinsse vould be the main thing thes I
would be looking for in the design of this exverinent and this aight be conplstely
indevendeant of antiviotic activity of the compound iteelf. As I understand it, the
princinal meghaniam of penieillin resistance in naturally occurring orgenians,
eeceelally the Stavhylocece!, is the formation of penicillinaee. Therefore { would
suggest that act only Fanide Wot ae large 5 variety of cenieillin-reianted coapcunde
ne cossible be sersened for their eceeific function in the inhibitien of cenieiliinese.
In fsot, this ie something whieh might well be keyed in with your general search for
satibletic activity, although the experinents mizht well be designed to vick wp
peniecillinase inhibition instead of antibiesis. I had the eane thine in alad in
referring to Cevhaleaperin WN ae another cotenti=1 comemund for this curveae. I know
fe: J. iein ~2e Fane 12, 1956

of practically ao attempts to sereen for peniolllinace inhibditers along theee lines
snd it coes not take mueh imagination te see both the nedteal and eeononic
roseibilities of euch a discovery.

I vas particnlarly glad to hear that I had misunderstoed the proper

channels of your work and thet you have considerable leqway in designing the areas
ef your exverimentation,

fours singerely,

Joebus
Wisle