EFFECTS OF MALONATE ON BACTERIAL INFECTIONS 221 



cutaneous injections of 0.4-0.8 g/kg of sodium malonate, almost all organs 

 being involved. Malonate is diuretic when subcutaneously injected into 

 hydrated rats at a dose of 11.5 millimoles/kg, this dose being sufficient to 

 inhibit kidney succinate oxidase (Fawaz and Fawaz, 1954). However, the 

 effect is probably osmotic rather than due to enzyme inhibition by the mal- 

 onate, since KNO3 at the same dosage induces the diuresis, and also be- 

 cause diethylmalonate, which inhibits kidney succinate oxidase, has no 

 diuretic activity. Summarizing these results, one may conclude that renal 

 damage may occur from high doses of malonate, but that minimal changes 

 in the kidney occur after the usual toxic doses. It seems unlikely that the 

 renal action is of major importance in poisoning or death from malonate. 



EFFECTS OF MALONATE ON BACTERIAL INFECTIONS 



The influence of enzyme inhibitors on the course of bacterial infections 

 is of great interest because the results have bearing on the fundamental 

 question of the metabolic basis of the resistance to infection. The effects 

 of malonate on Salmonella typhimurium infection in mice have been studied 

 by Berry and co-workers at Bryn Mawr in a series of excellent investiga- 

 tions. Mice injected intraperitoneally with a Salmonella suspension show 

 evidence of the infection on the third day and most succumb by the sixth 

 day. If mice are given intraperitoneal injections of 20 mg sodium malonate 

 in saline every hour for 8 hr, they die much more rapidly from the infection 

 than animals given only saline injections (Berry and Mitchell, 1953 a). 

 The striking effects is illustrated in Fig. 1-20. Noninfected mice show no 

 effects of the malonate. Thus sublethal doses of malonate are able either 

 to accelerate bacterial proliferation or to decrease the resistance of the 

 host markedly. These are the basic observations and the later work attempts 

 to elucidate the mechanisms by which these effects are brought about. 



The reduction of the survival time in mice infected with Salmonella is 

 not unique. Similar effects of malonate on infections with Proteus morganii, 

 Staphylococcus aureus, Streptococcus pyogenes (Berry and Mitchell, 1954), 

 Diplococcus pneumoniae, and Klebsiella pneumoniae (Berry et al., 1954 a) 

 have been observed. Furthermore, reduced survival times have been found 

 in Salmonella infected rats, guinea pigs, and chickens (Berry and Beuzeville, 

 1960). Finally, the phenomenon has been seen with other inhibitors, such 

 as fluoroacetate and arsenite (Berry et al., 1954 a, b). This, then, is a gen- 

 eral effect of certain types of inhibitor, especially those affecting the cycle 

 in some manner, and the problem is thus more important because it must 

 relate to some fundamental metabolic relationship between host and bacteria. 



We shall now examine in greater detail some of the characteristics of 

 the malonate effect. Malonate not only can reduce survival time, but in 

 some instances can change a nonlethal infection into a lethal one, this being 



