DIFFERENCES IN RESPONSE OF A VIRULENT STRAIN OF THE TUBERCLE BACILLUS AND ITS AVIRULENT VARIANT TO METABOLITES AND THEIR GENETIC SIGNIFICANCE

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Abstract
Of various amino acids (glycine, L-arginine, L-lysine, L-proline, hydroxy-L-proline, L-leucine, DL-leucine, DL-isoleucine, DL-valine, L-serine, D-threonine, DL-ornithine, DL-citrulline, L-glutamic acid (I), L-asparagine (II), DL-alpha-alanine (III), L-glutamine (IV), L-histidine (V), DL-aspartic acid (VI), DL- and L-threonine (VII), DL- and L-tryptophan (VIII), DL-methionine (DC), DL-norleucine (X), DL-serine (XI), beta-alanine (XH), DL-phenylalanine (XIII), and L-tyrosine (XIV)) tested, the 1st 13 had no significant effect on the rate of growth of either the H37Ra or H37Rv strain of the tubercle bacillus. Six (I-VI) increased the rate of growth of both strains, but only III stimulated one strain (H37Ra) and not the other. VIII and X inhibited both strains equally and Xt-XIV inhibited only H37Rv. Of the 17 other metabolites tested, only thymine, hypoxanthine, and nicotinic acid had a differential inhibitory effect, and none were stimulatory. Adenosine inhibited growth completely and produced lysis. When adapted to adenosine, H37Ra quantitatively converted adenosine to inosine. The latter was not inhibitory and apparently was not used by the organism. Adenine inhibited growth of both strains to a lesser extent than adenosine. Of 21 substances tested in the presence of adenine, 11 had a markedly greater effect on one strain than the other. The adenine effect is considered as being due to competition of adenine with adenosine triphosphate (ATP) rather than to interference with nucleic acid metabolism. Only methionine and choline antagonized the adenine-induced inhibition, and the antagonism occurred primarily in one strain (H37 Rv). Antagonists for the inhibiting amino acids are given, and evidence is presented for concluding that the inhibition by D-serine is not due to interference with the conversion of beta-alanine to pantothenic acid. On the basis of the observations it is postulated that the 2 strains differ in that H37Ra has lost the capacity to utilize phospholipids. It is further suggested that H37Rv possesses at least 2 pathways for acetylation, whereas H37Ra retains only the 1 involving condensation of alpha-amino acids with pyruvate. The hypothesis that there is numerical equivalence between cellular enzymes and genes is questioned on the basis of the observations made.

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