General Inquiries—4 1001: Ext. 31.
Professor of Bacteriology—41001: Ext. 41.

Professor of Bacteriology :
T. J. MACKIE, C.B.E., M.D., LL.D., D.P.H.

BACTERIOLOGY DEPARTMENT
UNIVERSITY NEW BUILDINGS
TEVIOT PLACE
EDINBURGH, I

 

Telephone Nos. :

 

Inquiries regarding Bacteriological Service,
S.E. Regional Hospital Board—4 2542.

23rd..September......19..55

Dear Professor Lederberg,

I apologise for being so long in replying to your letter but I
have been away on holiday and have only just now returned,

Thank you for your interest in my note in 'tature', The phenomenon
of apparent change in phage type was noted in this laboretory almost
accidentelly and has not been observed with all of our strains,

There are many streins which are penicillin-sensitive and of
Iysotypes belonging to Grp III, just as there are pen-resistant
strains of lysotypes belonging to Gp's I and II. Thus it is not a
simple relationship. The penicillin-sensitive Gp. III strains occur
fairly freavently emong the general population of this erea - say
15% of carrier strains, but they are not the same types as the Gp. III
strains which I find in hospital or obtain after exposure of sensitive
strains to penicillin.

However, one great difficulty in the interpretation of bacteriophage
typing of Staphylococci, is that since the reactions with Gp.III phage
are not well defined it is sometimes difficult to de@ide whether or not
a strain is different from another on the ~esis of minor, or even a

-major difference in the pheedly 4g pattern. For a time, when studying
the antibiotic-resistant strains"? a sin-le hospitel, I was of the
opinion that there was some sort of "gradation" of pattern with
differing antibiotic sensitivity, e.g. :

Type
Penicillin resistant ‘ ADL/5A/75
Streptomycin sensitive
Penicillin resistent
Streptomycin resistant AQ 750 76/99
Penicillin resistant Not
Streptomyc’n resistant typable
. —_ weak
Tetracycline resistant voaotions
to 76/77

but/
but exnerimental work has not given support to the view that these
differences: in phage: pattern could be acquired alon- with the acquisition
of resistance to semehityve antibiotics.

Suceessiv & .

On the whole I woul¢c agree with you that exposure to the drug
appears to be a condition for the change in phare type anc this is
further supported by the followinz evidence ( which may also fit with
the "prophege" theory ).

- phage

We occasionally observe spontaneous @#ekelysis in strains of
Staphylococei isoleted from cases. This phenomenon occurs with greater
frequency when the strains are exposed to penicillin of a certain
concentration, as occurs when we are carryins. out initial antibiotic-
sensitivity determinations, if the phage released et this phase is
separated from the parent culture it is usuelly founc to be of ¢p.III
and also similer to phages which now lyse the penicillin-resistant
variants.

Thus ,

+ 4 , Exposed to Penicillin-
original culture Penicillin. resistant
say of type 34, Autolysogenésis variant
resistant to phage 77 Phage separeted isoleted

and found to be
Sirilar to
Phage 77

not auto-
lysogeni¢.
type 77,
resistant to
phage 3A.

The problem warrants much closer looking into, and this we are doing.

a

I have sttempted to induce the resistance of Staphylococci to
bacteriophage and corr lated this with change in sensitivity to antibiotics,
but so far without clear-cut results. I have also carried out experiments
with antibiotic-sensitive and resistant strains isoleted from the same
environment to see whether cross-resistance and cross-chanses in phege
type could be induced, and also if there was any significant difference
between the two parent strains in these respects. The only setisfactory
evidence so far is in support of the comron fincing that penicillin
resistant Staphylococci ( i.e. penicillinase producers ) are frecuently
resistant to other antibiotics but venicillin-sensitive streins sre not (
under natural conditions). Unfortunately, peniciliinase production is
not a moropoly of Gr. TII lysotypes but does occur with Gp. I and II.

I/
3.

I shall study your most helpful suggestions on replica plating
and indirect selection. It would indeed be interesting to see if
spontaneous mute ,resistant to antibiotics retained their lysotynpe.

I enclose a copy of the note in Nature and some others which are
only indirectly concerned, but may possibly be of interest to you.
Most of my work on this problem has not yet been published, .

Yours sincerely,

Professor Joshua Lederberg,
Department of Genetics
University of Wisconsin
Madison 6,

Wisconsin,

U.S.A