1970 Volume 39 Issue 1 Pages 48-60
With the progress of metabolic and especially of histopathological investigations, a different view or diduction upon the mode of action of sulfones has been reported, in which it was advocated that the inhibitory mechanism of sulfones against leprosy bacilli differed from such a simple in vitro competition between sulfonamide and the folic acid biosynthesis by usual micro-organisms. Because the studies on the sulfonamide-type inhibition were still in limited status in the field of mycobacteria, a series of studies were performed step by step to elucidate these problems.
In this report, the inhibitory effect of DDS against the intake of some radioactive nutrients by numerous strains of mycobacteria was examined in comparison with that of s-DDS (DDS 2-sulfonamide) and DDSA (4, 4'-diaminodiphenyl sulfonamide), together with that of some PAS derivatives, two of them were newly synthesized.
As the result, the intake inhibition of PABA was generally found in the phase of partialy inhibited growth of mycobacteria. Whole the drugs employed except hydrazino-PAS derivatives showed this inhibition against all the strains employed, while only DDS was effective on leprosy patients or on the growth of leprosy bacilli in the footpads of mice. Also, this inhibition was limitedly seen in the case of Promin, even after 96 hours' incubation.
Although an inhibition of DDS against the intake of glutamate was slightly detected, the intake inhibition of tested nutrients other than PABA could not be clearly detected.
As for the PAS derivatives, PAS methylester (PASMe), whose carboxylic radical was masked, showed an intake inhibition of PABA, though it was somewhat inferior to that of PAS. Therefore, the relationship between the chemical structures of the PAS derivatives and their in vitro growth-inhibitory action on five strains of mycobacteria was examined, in which three strains of human tubercle bacilli showing resistance to some antituberculous drugs were included. As the result, it was found that PAS hydrazide (PASH) had the highest action even on PAS-resistant strains and that PASMe showed an effect similar to PAS. However, the derivation of the NH2-radical of the PAS derviative into the corresponding hydrazine compound brought about a lowering of the action. while, in the case of sulfones and sulfonamides, it was well-known that this derivation brings about a favorable result. The result of IR spectrophotometric analysis showed that only PAS formed an intramolecular hydrogen bond among these PAS derivatives. Thus, the mechanism of the in vitro action by PASH was supposed to be different from that by PAS. Both the hydrolysis of PASMe into PAS and the decarboxylation of PAS by M. phlei growing in Dubos' broth nutrient fluid could not be detected.
To find out any relation between these in vitro results and the mode of action of sulfones in vivo, at the first step, the distribution of 3H-labled Promin in leprous nodules of 17 leprosy patients was examined, and it was found that the effective concentrations of DDS in Promin were calculated to be only 3-4μg at 1 hour, 1.5-0.5μg at 6 hours, and below 0.5μg at 12 hours per 1g (wet weight) of each nodule after an injection.
Based on these results, a bacteriological re-consideration was mentioned, especially concerning the relation between the mode of action of sulfones in vitro and in vivo.
