174 Perspecfives in Microbiology 



question of permeability, for cell-free sonic extracts also 

 combine with the antibiotic in relation to the sensitivity 

 of the parent organism. Highly significant in this connec- 

 tion is the fact that no matter what the sensitivity, that is, 

 no matter what the combining affinity with penicillin, bac- 

 teria are regularly killed when they have combined with 

 1.4 to 2.2 [xg per gram, equivalent to 1500 to 2800 mole- 

 cules of penicillin per cell. In four different species, 900 

 to 1250 molecules were found to be bound per cell with- 

 out producing a demonstrable effect on growth; when the 

 bound penicillin reached 1500 to 1700 molecules per cell, 

 there was a marked inhibition of growth; and the bacteri- 

 cidal action reached maximal levels when the bound peni- 

 cillin was 1500 to 4000 molecules per cell. Bacteria as they 

 occur in nature, therefore, only appear to differ in their 

 sensitivity to penicillin. They actually differ wdth respect to 

 the concentrations that must be present in the outside 

 medium to effect the uniformly lethal degree of combina- 

 tion with the cell. 



Here, then, is the mechanism of selective toxicity origi- 

 nally postulated by Ehrlich, a selective toxicity not based 

 on differences in growth requirements, metabolic path- 

 ways, or cell permeability, but rather based on differences 

 in the chemical reactivity of a vulnerable cell component 

 in the resistant and sensitive species. 



The nature of the penicillin-reactive component and of 

 the metabolic reaction that is thereby inhibited remains 

 to be determined. 



The relative nontoxicity of penicillin for the mam- 

 malian host apparently rests on a similarly weak combining 

 reactivity between penicillin and the cell. As in highly 

 resistant bacteria, the concentrations inside the cell are 

 regularly less than those in the surrounding medium and 

 are consistent with a simple diffusion equilibrium. Most 

 of this cellular "penicillin" is readily eluted on washing, 

 is actively bactericidal, and is presumably the free and 



