49. Bacterial Inhibition by Metabolite Analogues

The production of growth-inhibiting agents by suitably modifying the structures of growth-promoting substances has been shown to be feasible by previous investigations (Mcllwain [1940; 1941a]: considered -as parts 1 and 2 of the present series). In these cases evidence was obtained which showed that the inhibitory analogues produced their effects by limiting the organism's use of the corresponding essential substances. Pantothenic acid was chosen as subject for extending these investigations as it is essential for the growth of many disease-causing organisms: for Streptococcus haemolyticus, for Diplococcus pneumoniae [Rane & Subbarow, 1940]; for initial growth of Staphylococcus aureus; for Clostridium tetani [Mueller & Miller, 1941] and Clostridium welchii [Tamura, Tytell, Boyd & Logan, 1941]; for certain strains of Corynebacterium diphtheriae [Evans; Handley & Happold, 1939], some members of the Pasteurella [Berkman, Saunders & Koser, 1940] and Brucella [Koser, Breslove & Dorfman, 1941] groups and for Proteus morgani [Pelczar & Porter, 1940]. The analogues tested are related to pantothenic acid (I) in the folowing ways. (a) Homologues. The belief that compounds so related might be inhibitory was based on the report of Robinson [1940] that a ,B-tri-substituted propionic acid was inhibitory to growth of Mycobacterium tuberculosis of which phthioic acid, a trisubstituted acetic acid, is a normal constituent. Inhibition of succinic dehydrogenase by malonate affords a further example, and more recently ethionine, C2H5 .S . CH2. CH2. CH(NH2JCOOH, has been found to limit bacterial growth by competition with methionine [Harris & Kohn, 1941]. y-Hydroxy-n-butyrylf--alanine, (II), a bisnordesoxypantothenate; y-hydroxyn-valeryl-/3alanine (III), an isonordesoxypantothenate; homopantothenate, (IV) and a desoxypantothenate (V) were accoidingly tested. (b) Related olefin. Fildes [1941] showed that indoleacrylate inhibited bacterial growth by virtue of its relation to tryptophan. The structure of pantothenate precludes the production of an olefin by simpleelimination of H20 or NH3, but dehydrohomopantothenate (VI), which is so related to homopantothenate, was tested. (c) Sulphonic acids and sulphonamide. Several models are available: Woods [1940] showed sulphanilamide inhibition to be related to p-aminobenzoic acid; some aliphatic oc-aminosulphonic acids inhibit by virtue of their relation to oc-aminocarboxylic acids [Mcllwain, 1941a], and pyridine-3-sulphonic acid and its amide by their relation to nicotinic acid and derivatives [Mcllwain, 1940]. The latter instance served as model for Snell's [1941] production of an inhibitory analogue of pantothenic acid, which was published while these investigations were in progress. Analogue VII, which it is proposed to call pantoyltaurine (pantoic acid=oc:y-dihydroxy-3:f-dimethylbutyric acid) is the analogue investigated by Snell. Detailed results of its effects on pathogenic organisms have been reported elsewhere [Mcllwain, 1942b] and are referred to here for comparison only. In addition, the corresponding sulphonamide (pantoyltauramide, IX) and a homologue (homopantoyltaurine, VIII) have now been tested. Taurine and taurine amide, which are the sulphonic acid and sulphonamide corresponding to f-alanine, a component