Magic bullets and moving targets: antibiotic resistance and experimental chemotherapy, 1900-1940.

It was in the 1940s that antibiotic resistance arose as an object of study for clinical medicine. Somewhat earlier it had become an important analytical tool for bacterial geneticists. However, the concept of antibiotic resistance as an induced and inheritable trait of microbial species was introduced a generation earlier in the years preceding the First World War. The paper reconstructs the concept that was put forward by the German immunologist Paul Ehrlich in 1907. He came across the phenomenon when trying to develop chemotherapies for trypanosomiasis, the best known of which is African sleeping sickness. However, resistance was studied by him for other than therapy-related purposes. It provided a productive laboratory model for the study of cell functions. Induced resistance to chemicals facilitated the development of ideas on the relation of a parasite's cellular metabolism and of drug action, i.e. by providing a negative proof for the existence of chemoreceptors on the surfaces of parasite cells. This approach does also serve to explain why British and German researchers continued to study the phenomenon of induced resistance in microbes for decades -despite it being absent from clinical medicine. After all, there existed very few chemotherapies of infectious diseases prior to the arrival of the sulfa drugs. Moreover, resistance to such medicines was rarely observed. However, being part and parcel of Ehrlich's theories, his views on resistance were also criticised together with these. It was in particular Henry Dale who would challenge Ehrlich's views of resistance being an inheritable and stable trait of microbes. Instead he insisted that understanding this "wholly mysterious phenomenon" required taking into account some host interaction. Induced resistance, which had come into being as a chance discovery on the chemotherapy of sleeping sickness, thus became one of the more important laboratory models of twentieth-century immunological research. Its early history is largely discontinuous with later work, and antimicrobial resistance as it evolved from 1900 to 1940 followed other trajectories than those which became relevant after 1940.