EFFECTS OF MALONATE ON BACTERIAL INFECTIONS 223 



The rapid proliferation of bacteria could be due to a weakening of the 

 body defenses for disposing of the bacteria. This does not seem to be the 

 case, inasmuch as malonate has no effect on the uptake of thorotrast by 

 the reticuloendothelial system (Berry, 1955) nor does it depress phagocytosis 

 except at very high concentrations (Berry and Derbyshire, 1956). Instead it 

 would appear that malonate disturbs metabolism in such a way that it 

 creates a more favorable environment in the host for bacterial growth. 

 Malonate itself may be metabolized slightly by Salmonella, but not to the 

 extent required to explain the explosive proliferation (Berry and Beuzeville, 

 1960). Growth medium was prepared from the eviscerated carcasses of con- 

 trol and malonate-treated animals and it was found that the bacteria grow 

 more rapidly in the latter (Berry, 1955). It has also been shown that Sal- 

 monella grows more rapidly in the peritoneal fluid of malonate-treated mice 

 than in the controls (Berry and Beuzeville, 1960). Citrate is known to ac- 

 cumulate following the administration of malonate. This was confirmed in 

 mice given the doses of malonate capable of reducing survival times of 

 infected animals (Berry et al., 1954 b). Both malonate and endotoxin from 

 Salmonella increase citrate levels in most tissues, and together the increases 

 are often greater than with either alone (see accompanying tabulation). It 



Treatment 



Citrate (//g/g) in 



Blood Spleen Kidney Heart Duodenum Liver 



132 109 



115 170 



170 443 



543 240 



is thus possible that a summation of effects on the cycle could be partially 

 responsible for the increased mortality. However, Salmonella infection does 

 not increase citrate levels (Berry and Beuzeville, 1960). Could the increased 

 citrate be favorable to the growth of the bacteria? It is unlikely that this 

 is a major factor because malonate is the most potent inhibitor for reducing 

 survival times and yet both arsenite and fluoroacetate cause greater accu- 

 mulations of citrate. The primary cause of the augmented bacterial proli- 

 feration has not been found but the range of possible mechanisms has been 

 narrowed. Since there are many other possible substrates for Salmonella 

 that accumulate during malonate inhibition, it will be necessary to examine 

 these in mice and their effects on the growth of Salmonella. 



Some work on this problem in other laboratories may be briefly mention- 

 ed. Malonate reduces the antibacterial activity of guinea pig blood toward 



