Theoretical Aspects of Bacterial Chemotherapy

Abstract

Summary Higher organisms and micro‐organisms exhibit many types of mutual action and association, and that type of interaction in which the micro‐organism becomes a parasite is normally prevented by the potential host. If parasitism is established its course may be impeded by administration of substances to the host; interaction in the resulting system of drug, parasite and host then constitutes chemotherapy. The interactions of successful bacterial chemothera‐peuticals with the parasites, apart from the host, show characters which in most cases afford a basis for their effects in vivo. Their action may be to retard bacterial growth, as is the case with sulphonamides. They may stop the use by the parasite of substances which protect it from the host, as do the antipneumococcal polysaccharidases; or they may react with bacterial products which are injurious to the host, as do antitoxins. Such actions are susceptible to further analysis. The effects upon growth have been found to be associated with particular substances whose nature in several cases has suggested the mode of action of the inhibitor. Hypotheses based upon such findings have enabled certain new types of agents to be prepared, and reasons given for their structural specificity. Processes of the parasite, which are affected by chemotherapeuticals, have also been characterized by following the influence of the agents upon the course of growth of the parasite. A beginning has been made to specifying such influence in terms of effects upon isolated metabolic processes and other events in the parasite. Interaction of the host with both parasite and antibacterial agent or potential agent condition the issue in chemotherapy. The concentrations of effective agent reached at different times in different parts of the host depend upon characters which are open to experimental modification, such as the mode of administration of the agent, but also upon many which are not. The latter may be accommodated by suitable choice or design of agent and include its physiological characters such as absorption, excretion and reabsorption, and biochemical ones such as its activation or inactivation by substances or processes of the host. It is necessary to study these factors, and other undesirable reactions with the host, before correlation of chemotherapeutic efficacy with structure of the agent can be expected. Events in the complete chemotherapeutic system have been referred to properties of its components by observations which include: correlation of the actions of an agent upon the parasite in vivo and in vitro; the reproduction in vitro of synergism and antagonism observed in chemotherapy; the finding of in vitro phenomena associated with drug resistance in vivo; and the type of change in the host associated with success of chemotherapy or with normal recovery from, and resistance to, infection.

Metabolite Antagonists.

“…Some of the later studies in these fields are incorporated in Section IV. A number of articles summarizing a portion of the work with other metabolite antagonists, particularly in relation to antibacterial action, have appeared (6,7,94,199,205,256,257,261,425,428,451). The reader is referred to these summaries for brief discussions of this phase of the subject.…”