Physiological Mechanisms of Resistance 167 



arise by mutation, and since certain other mutations were 

 shown to have an all-or-none effect on the formation of a given 

 enzyme. However, it has become abundantly clear that 

 the biochemical consequence of mutations is by no means 

 restricted to such an all-or-none effect, and so this mechanism 

 has lost much of the basis for its appeal. Furthermore, there 

 are definite reasons to doubt whether this mechanism occurs 

 at all. For in a biosynthetic sequence proceeding from com- 

 pound A to C via B, the appearance of a new route bypassing 

 B would surely have to involve the insertion of more than one 

 new enzyme in the sequence. Of course, it is possible that one 

 or more of these enzymes, though new in the sequence, 

 might already be present in the cell for other purposes. The 

 theoretical objection to this mechanism is therefore not 

 absolute ; but it should be added that the mechanism has not 

 been clearly demonstrated in any case with which the present 

 author is familiar. 



Mechanism 2, increased concentration of a competitive 

 metabolite, has also had widespread appeal ever since sul- 

 phonamides were shown to act by competing with ^-amino- 

 benzoate (PAB). However, in the few cases where increased 

 formation of PAB has been demonstrated the effect has been 

 too slight to explain more than a trivial increase in resistance. 

 Furthermore, despite much effort none of the antibiotics have 

 been shown to act by competing with a metabolic intermediate. 



The next two mechanisms, increased concentration of the 

 enzyme or decreased requirement for its product, could also 

 hardly be expected to produce more than a modest increase in 

 resistance. 



Mechanism 5, destruction of the inhibitor, has been shown 

 to be important in some penicillin-resistant strains, which 

 form and excrete the enzyme penicillinase. The behaviour of 

 such strains is dealt with in detail elsewhere in this symposium 

 by Dr. Pollock (p. 78) and by Dr. Barber (p. 262). 



And now we come to the last two mechanisms, which 

 involve principles that have become established in micro- 

 biology only in the past few years : the ability of mutations to 



