Infectious multiple drug resistance / S. Falkow.

  • Falkow, Stanley.
Date:
1975
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Infectious multiple drug resistance / S. Falkow. Source: Wellcome Collection.

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    1 Historical perspective - drug resistance and R-factors The use of sulphonamides and antibiotics has had an enormous influence on the pattern of infectious diseases throughout the world. We owe chemotherapy the debt of reducing the high mortality rate of many bacterial infections; but in helping to solve some of the problems of infectious disease, chemotherapy has created some problems of its own. One of these problems, a central theme of this book, has been the appearance of strains of organisms resistant to certain drugs. Apart froî^ its obvious medical importance, the study of the genetic and biochemicál basis of microbial drug resistance provides an important, unexpected, and, I think, exciting avenue to several aspects of fundamental biology. Two alternative theories were initially advanced to explain the origin of microbial resistance to drugs. One view held that the resistant cells developed by spontaneous mutation independent of the presence of the drug. The other view held that the resistant cells were the adaptive product of interaction between the drug and bacterial cell. In 1943 the fluctuation test of Luria and Delbrück provided the first critical evidence to distinguish between the mutational and adaptive theories. The evidence presented by these workers was statistical in nature and indicated that resistant variants were present in the bacterial population before exposure to drugs and were therefore spontaneous mutants. These statistical findings were strengthened by the technique of indirect selection, which permitted the isolation of resistant clones that had never been in contact with a drug and could not have arisen by adaptation. This application of fluctuation analysis, and of indirect selection to the development of microbial resistance to sulphonamides, penicillin, streptomycin, chloramphenicol, and other drugs was consistent with the mutation hypothesis. Thus it became a general assumption that antibiotic resistance in microorganisms had developed solely by the selection of random spontaneous mutants in response to widespread chemotherapy and had evolved almost entirely within the past thirty years. It seemed logical to conclude that studies in vitro of mutation to drug resistance would serve as the basis of explanation for the behaviour of organisms under natural conditions. A single-step pattern of high resistance to streptomycin was demonstrated by fluctuation analysis. On this basis one would suspect that bacterial resistance in vivo to streptomycin would be a common event and, indeed, it is established that the rapid emergence of resistant strains to this drug forms the main obstacle to its successful use clinically. Other studies in vitro showed, however, that a single mutational event often resulted in only a slight increase in drug resistance and that a number of sequential mutations were usually required before a sensitive organism developed a high level of resistance. This multi-step pattern of accumulating resistance by successive increments was