Mechanisms of drug resistance (Dr. E.M. Lederberg)

The importance of the development of drug resistant strains of bacteria
ain the long-term success of chemotherapy 1s now well recognised but the
biological tasis of the development of drug-resistant strains has been the
subject of bitter controveray for several yeers. One of the reasons that
this question has been mooted for so long has been that, ordinarily, the only
means by which a drug-resistant mutant strain of a bacterium could be
produced in the laboratory was by exposing e culture of the bacteria to the
drugs This left open the question as to whether a very small number of
spontaneously occurring resistant mitants had been already present in the
treated bacterial populetions prior to exposure to the drug, or whether the
drug itself played some specific role in inducing the adaptation. Many
indirect lines of evidence had alreedy pointed to the validity of the former
mechaniam but many workers continue to insist on the latter, pointing to the
absenee of any direst preoef of the spontaneous occurrence of drug-resistant
mutants. Thies difficulty has been circumvented by the development of the
new method, “indirect selection", which is based on the technique of
"“yeplica plating" for faithfully transferring a whole pattern of bacterial
growth from one Petri dish to another by means of a sheet of velvet. This
has now allowed an indirect method of selection of resistant mutants based
on going back to the sites on a plain agar plate where resistant mutants are
indicated to be by tests on replicas and ultimately, thus, to isolate drug
registant mtants from bacteria that have never been directly exposed to
the drug. These experiments which were initially done in our laboratory
with streptomycin and Escherichia coli have since been confirmed and extended

by several other workers.