DRUG RESISTANCE 151 



A disadvantage of streptomycin is its toxicity. Especially when administered 

 over a prolonged period as is necessary in the case of many tubercular infectious 

 neurotoxic effects are observed. The reduced compound dihydrostreptomycin is,. 

 however, less toxic and this is now undergoing clinical trial. 



MECHANISM OF ESTABLISHMENT OF DRUG RESISTANCE 



Bacteria can acquire resistance to drugs in several ways, for example : — 



(1) By becoming less permeable to the drug so that it cannot gain access tO' 

 vulnerable systems in the organism. 



(2) By the vulnerable part of the organism becoming less sensitive. For 

 example, if the drug exerts its action by interfering with one enzymic reaction 

 in a synthetic chain the organism may substitute another reaction which 

 by-passes the vulnerable reaction. 



(3) By developing a mechanism for inactivating the drug. For example, 

 staphylococci develop an enzyme penicillinase which destroys penicillin when 

 the staphylococci develop penicillin-resistance, as they do very readily. 



There are two methods in which bacteria can develop resistance : they can 

 develop resistance gradually, each organism in a culture developing by imperceptible 

 stages greater resistance to the drug, or they can develop resistance by mutation. 

 In the latter case, which appears to be considered the actual mechanism observed, an 

 occasional organism, perhaps only one in a million, by a random mutation acquires 

 resistance to the drug, and wdien the drug is present the resistant organism and its 

 progeny will survive whilst non-resistant organisms perish. The resistance is inherited 

 by the cells formed by sub-division of the resistant mutant so that a resistant strain 

 is established. Of course, a mutant may arise in the resistant strain and the mutant 

 may not be drug-resistant, but such a mutant would be difficult to detect and if 

 subcultured in the presence of the drug would not survive. Hence reversion of drug- 

 resistant strains to drug-sensitive is not commonly observed. 



Gale and Rodwell (1949) summarise the action of penicillin on Staphylococcus 

 aureus as being due to interference with the assimilation of glutamic acid. Resistant 

 strains do not actively assimilate glutamic acid, but synthesise the amino acid from 

 glucose and ammonia. Hence the development of resistance to penicillin is associated 

 with the development of the synthetic mechanism by which an essential amino acid 

 can be produced in the cell, which thereby becomes independent of external supplies of 

 glutamic acid and resistant to the assimilation-inhibitory effect of the antibiotic. 

 It seems possible that penicillin may interfere with the cell membrane by inhibiting 

 the enzymes responsible for the deamination-reamination process which, it has been 

 suggested, is necessary for passage through the cell wall. Reverse mutation of resis- 

 tant cells by which synthetic ability is decreased leads to increased penicillin resis- 

 tance. Hence a consistent scheme of explanation of the phenomena has been provided. 

 The additional method of developing resistance by production of a penicillin-destroy- 

 ing enzyme, penicillinase, is presumably entirely a separate phenomenon. 



A rather remarkable feature of some bacteria which develop resistance tO' 

 streptomycin is that they become streptomycin-dependent. That is to say they will 

 only grow in the presence of streptomycin and streptomycin has become a necessary 

 growth factor for such bacteria. Apparently some micro-organisms never exposed tO' 

 streptomycin also utilise it as a growth factor. 



