A Means of Increasing the Tuberculostatic Effect of Known Chemotherapeutic Agents

Abstract

Dubos and his coworkers recently have shown the profound influence that certain surface-active oleates have on the in vitro growth of the tubercle bacillus (1-3). Their work suggests that by the addition of these fatty acid in a highly surface-active form a great enhancement of growth can be obtained. The mechanism of action of this surface-active growth-promoting factor has been interpreted according to known physical-chemical principles, which would indicate that the oleate is concentrated at the periphery of, or within the confines of the mycobacterium.In the study here to be reported, 1 several surface-active tuberculostafic substances have been prepared and tested in an effort to determine whether a similar increased effect on the tubercle bacillus would be obtained by concentrating an inhibitory instead of a stimulating substance about the organism.These substances were found to be effective in vitro in relatively low concentrations.The mechanism of such tuberculostatic action was investigated according to physical-chemical principles, by isolating the factor of drug action due to its surface activity from its inherent (non-surface-active) component. This was carried out by introducing a substance antagonistic to the surface-active component of the drug, but in no other way interfering with its antibacterial action. These studies suggest that the property of surface activity may enchance the tuberculostatic action of a given drug. The reason for such action is discussed and correlated with the steric arrangement of the drug molecule in relation to the surface of the mycobacterium. Other previously described surface-active tuberculostafic chemicals and antibiotics have also been studied with this concept in mind, and certain of them are shown to owe a part of their activity to the surface-active character of their molecules. Hypothethical Effect of Surface-Active Substances upon Mycobacteria.--Ingeneral, studies of the effects of surface-active substances upon the growth of bacteria and of acid-fast organisms in particular (4--8) have emphasized the fact that human tubercle bacilli can grow in vitro at a vastly reduced surface

The Colloidal Phenomena of Antibiotics.

“…As might be expected, this was most pronounced in the case of maximum concentration and large micelle size, while at the lower concentrations a longer period of time was required before there was 0 <0 OOO ¿0 000 JO 000 40 000 ¿0 000 «0 000 fftvcf-v Tf>A non, units /cc Fig. 4. Absolute viscosity of aqueous sodium penicillin dihydro F at various concentrations.…”

“…The results for sodium penicillin dihydro F are shown in table 4 and plotted in figure 4. The shape of the curve was found to be the same as for the other types of penicillin.…”

THE IN VITRO EFFECT OF ANALOGS OF VITAMIN K ON MYCOBACTERIUM TUBERCULOSIS VAR. HOMINIS, STRAIN H37Rv

“…compounds studied was the possession of a free amino group in the 6 position. Eiseman (1948), in attempting to increase the tuberculostatic effect of sulfonamide derivatives by attaching the hydrophobic end of the molecule to a surfaceactive molecule, stated that a free amino group was required for optimum action. The general antibacterial properties of "synkamin" were discussed by Schwartzman (1948).…”