ORIGIN OF BACTERIAL RESISTANCE TO ANTIBIOTICS 1 



M. DEMEREC 

 Department of Genetics, Carnegie Institution of Washington, Cold Spring Harbor, New York 



Received for publication March 29, 1948 



In this brief review of the problem of the genetic aspects of the origin of bac- 

 terial resistance to antibiotics, I intend to discuss mainly work done in my lab- 

 oratory. I shall (1) offer evidence that bacterial resistance to penicillin and 

 streptomycin is not induced by these compounds but originates spontaneously 

 through genetic changes comparable to gene mutations; (2) describe the resist- 

 ance patterns observed in experiments with penicillin and streptomycin; and 

 (3) outline a possible mechanism responsible for resistance, and for the differ- 

 ences between the resistance patterns observed with penicillin and those observed 

 with streptomycin. 



All experiments were done in vitro. Penicillin was tested with Staphylococcus 

 aureus, strain NRRL 313 (Demerec, 1945a), and streptomycin was tested with 

 the same strain of S. aureus and with Escherichia coli, strain B. The strep- 

 tomycin was obtained from Chas. Pfizer & Co., New York, at a time when this 

 compound was still very scarce, and I wish here to acknowledge their generosity. 

 In all the experiments bacteria were first grown in broth cultures without any 

 penicillin or streptomycin ; these were used only in the tests for resistance, made 

 by growing bacteria on broth agar plates containing various concentrations of 

 one or the other antibiotic. 



SURVIVAL CURVES 



Figures 1 and 2 show the behavior of our strain of S. aureus when plated on 

 nutrient agar plates to which specified amounts of penicillin (figure 1) or strep- 

 tomycin (figure 2) had been added. It is evident from these curves that on low 

 concentrations of either antibiotic all bacteria survived and formed colonies. 

 Threshold concentrations are indicated on the curves by sharp breaks, the num- 

 bers of survivors decreasing very rapidly with increase of concentrations. The 

 slope of the curves is very steep at concentrations near the threshold, but levels 

 out as concentrations become increasingly higher. These curves show that we 

 were dealing with mixed populations of types sensitive to antibiotics and types 

 more or less resistant. Sensitive bacteria made up by far the largest portion of 

 the populations. 



The two curves are very similar in the region of lower concentrations. A 

 striking difference is evident, however, in the region of higher concentrations; 

 on the medium containing streptomycin, survivors continued to appear even at 

 the highest concentration used in the experiments. 



1 Substance of a paper delivered at the Symposium on Antibiotics at the Chicago meet- 

 ing of Section N of the American Association for the Advancement of Science, December 30, 

 1947. 



63 



[Reprinted by permission of The Williams & Wilkins Company from Journal of 

 Bacteriology 56 : (1) 63-74, July, 1948] 



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