XIV. THKKAPHITK" ACTIVITY 81 



iniiiislercd orally al '2- to :i-hoiir iiitcrxals for a total daily dose of 25 to 



The moc'haiiisni by which I'AHA acts to iiihil)it, rickettsia is not known, 

 but recent work of Davis and colleagues has thrown some light on the sub- 

 ject. For the W strain of Kschcrichin coli Davis showed'^- ■** tliat PABA is a 

 bacteriostatic compound. The bacteriostatic activity of PABA is reversed 

 by p-hydroxybenzoic acid (POB). Separate studies by Davis showed pre- 

 viously^^ that for certain mutants of Escherichia coli with a requirement for 

 five aromatic compounds (quintuple aromatic auxotrophs) POB is a bac- 

 terial vitamin essential for rapid growth. Shikimic acid and compound X, 

 previously shown by Davis et al. to be precursors of the aromatic ring in 

 Escherichia coli, similarly are active in the reversal of PABA inhibition. 

 Thus it would appear that POB is an essential metabolite for which PABA 

 is a naturally occurring antimetabolite. This concept is sHghtly compli- 

 cated but not necessarily vitiated ]:)y the fact that POB may be derived 

 from PABA at a slow rate. As summarized by Davis,*^ it would appear 

 that PABA exerts three metabolic effects on Escherichia coli: it acts as a 

 normal vitamin at low concentrations, as a source of another vitamin, 

 POB, at moderate concentrations, and as a growth inhibitor at high con- 

 centrations. 



Snyder and Davis have published a preliminary note^° concerning the 

 extent to which the metabolite-antimetabolite relationship between POB 

 and PABA established in Escherichia coli can explain the rickettsiostatic 

 effect of PABA. POB was found to reverse PABA in two tests with the 

 Breinl strain of epidemic typhus in chick embryos, in one test with murine 

 typhus in white mice, and in one test with Rocky Mountain spotted fever 

 in chick embryos. For reversal of rickettsiostasis in chick embryos, the 

 effective ratio of POB to PABA (on the basis of the amounts inoculated 

 into each egg as a single dose at zero time) appears to be in the range of 

 1:1 to 1:10. 



B. RHEUMATOID DISEASES 



PABA has shown some promise in the treatment of acute rheumatic 

 fever. Dry el al}^ encountered a case of acute rheumatic fever in an adult 



** N. A. Tierney, Southern Med. J. 40, 81 (1947). 

 •5 N. A. Tierney, /. Am. Med. Assoc. 131, 280 (1946). 

 '« A. Yeomans, J. Am. Med. Assoc. 126, 782 (1944). 

 '" B. D. Davis, Federation Proc. 10, 406 (1951). 

 '"" B. D. Davis, J. Exptl. Med. 94, 243 (1951). 

 ^9B. D. Davis, Nature 166, 1120 (1950). 



" J. C. Snyder and B. D. Davis, Federation Proc. 10, 419 (1951). 

 =• T. J. Dry, H. R. Butt, and C. H. Scheifley, Proc. Staff Meetings Mayo Clinic 21. 

 497 (1946). 



