484 CHEMICAL AGENTS 



Liebermeister (225) has proposed that several drugs effective against 

 Mycobacterium tuberculosis are also active by virtue of their formation 

 of a toxic complex. 



Some of the detailed data on the action of the dithiocarbamates is 

 inconsistent with, or at least not explained by, the theory of action just 

 outlined. These data are thoroughly reviewed by Horsfall (174), and 

 it should be clear that many problems remain. No other hypothesis, 

 however, explains the bimodal dose-response curve. 



Imidazoles, which are themselves complexing agents, antagonize the 

 action of DMDT in the concentration range of the first peak of toxicity 

 (198). This suggests that the locus of toxicity of the 1:1 copper chelate 

 is an enzyme which is normally coordinated to some metal, and that the 

 available coordination positions of the copper in the 1:1 complex re- 

 place the metal on the enzyme. 



Dithiocarbamates at minimally fungistatic concentrations have very 

 slight activity against endogenous or glucose respiration in fungi (81, 

 127, 203, 314). Acetate oxidation in yeast is considerably more sensi- 

 tive (127). The respiratory enzyme triose phosphate dehydrogenase is 

 inhibited in yeast and in Fusarium roseum by TMTD (384, 385). This 

 may be explained on the basis that the dithiocarbamates react with 

 glutathione (432) and that the reduction of TMTD to DMDT (Equa- 

 tion 8) is likely to be coupled to an oxidation of such labile cell mate- 

 rials as glutathione. Since glutathione is the prosthetic group of triose- 

 phosphate dehydrogenase (210), it follows that this enzyme will be- 

 especially sensitive. It must be concluded that we are at present unable 

 to point to any specific system, the inhibition of which is the primary 

 effect of either free dithiocarbamates or their active complexes. 



The present picture of the action of fungistatic chelating molecules 

 is thus one of great complexity. A given compound exists as an anion 

 or as an uncharged molecule and as complexes of various metal :ligand 

 ratios with one or more metals. One or more of these molecular species 

 reaches the sensitive region of the cell, at which point a new set of 

 equilibrium conditions, complicated by the presence of cellular chelat- 

 ing agents, must be envisioned. Still other complications can be intro- 

 duced by structural alteration of the chelating agent; such structural 

 changes influence ionization, water and lipoid solubility, and the sta- 

 bility of metal complexes. 



Although the bisdithiocarbamates are superficially similar to the 

 dithiocarbamates and are also chelating agents, the evidence to date 

 suggests that the mode of action is not the same. In particular, fungi 

 show different sensitivities to the two classes of toxicant, for a given 

 fungus the slopes of the dose-response curves are different, and the 



