Activity of selected beta-lactam antibiotics against Mycobacterium leprae.

Twelve beta-lactam antibiotics were tested for activity against Mycobacterium leprae growing in the foot pads of mice. Two cephalosporins (7-aminocephalosporanic acid and cefuroxime) and one cephamycin (cefoxitin) showed significant activity against M. leprae, and one penicillin (mezlocillin) exerted possible growth-promoting activity. These results suggest that particular molecular structures may be required for activity against M. leprae.

Susceptibility of strains of Mycobacterium leprae isolated prior to 1977 from patients with previously untreated lepromatous leprosy.

Because of the recent spate of reports of primary resistance to dapsone among patients with lepromatous leprosy, largely to small concentrations of the drug, a survey was made of the results of dapsone-susceptibility testing of strains of Mycobacterium leprae isolated before 1977 among six laboratories which employed the mouse foot pad technique for this work prior to that time. Data have been found for strains that had been isolated from 73 patients, representing 19 countries and dependencies, with previously untreated lepromatous leprosy; all 73 strains were inhibited from multiplication by dapsone administered to mice in a concentration of 0.0001 g per 100 g mouse diet. These data suggest that the properties of M. leprae isolated from previously untreated patients with respect to susceptibility to dapsone have changed since the years preceding 1977.

An experimental study of the antileprosy activity of a series of thioamides in the mouse.

A series of substituted thioamides have been studied to establish whether their structure-activity pattern against Mycobacterium leprae is similar to that displayed against M. tuberculosis. Antileprosy activity was evaluated in the mouse foot pad using both the kinetic and continuous methods. Ethionamide and prothionamide were found to be the most active compounds and to be of approximately equal potency. Thioisonicotinamide was about five times less active. 2-t-Butyl-thioisonicotinamide, 2-dimethylamino-thioisonicotinamide, and pyrazine carbonic thioamide were inactive at the dosages tested. High-pressure liquid chromatographic methods were devised to study the potential influence of pharmacological factors on their in vivo activity. Fecal measurements suggested that all of the thioamides were well absorbed when fed in the diet. After intravenous administration, all of the thioamides were rapidly eliminated from the mouse. The differences in their elimination rates probably played only a minor role in affecting their relative antileprosy activities. It was concluded that the structural requirements for antileprosy and antituberculosis activity of the thioamides are probably similar.

Toxic effect of the peroxidase-hydrogen peroxide-halide antimicrobial system on Mycobacterium leprae.

Mycobacterium leprae are killed by myeloperoxidase (or eosinophil peroxidase), H2O2, and a halide, thus suggesting a mechanism for their destruction by peroxidase-containing phagocytes.

2-Acetylpyridine thiosemicarbazones and Mycobacterium leprae.

Four 2-acetylpyridine thiosemicarbazones were tested in mice against Mycobacterium leprae by the kinetic method and found to be nearly inactive in a dosage of 0.05% in the diet. At the same dosage, thiacetazone, as a positive control, exhibited its expected activity.

Comparison of the immunogenicity of vaccines prepared from viable Mycobacterium bovis BCG, heat-killed Mycobacterium leprae, and a mixture of the two for normal and M. leprae-tolerant mice.

Intradermal vaccines consisting of viable Mycobacterium bovis BCG, heat-killed Mycobacterium leprae, or mixtures of the two were titrated in mice in doses of 10(5.2), 10(5.8), 10(6.4), 10(7.0), and 10(7.6) acid-fast bacilli. The immune response was measured by sensitization (48 to 72 h foot pad enlargement on challenge with 10(7.0) heat-killed M. leprae) and by protection against infection with a viable M. leprae challenge. There was increasing response with increasing dose of vaccine, and overall the responses to the three vaccines were similar. At the lowest dose, however, the combination of BCG and M. leprae gave superior protection. The local reaction to the vaccines in the lower dose range was less severe with the M. leprae vaccine. In another experiment, the three vaccines were compared in normal mice and in mice that had been rendered tolerant by intravenous injection of M. leprae. The tolerant mice developed no measurable sensitization on vaccination with M. leprae, but they developed partial but distinct sensitization on vaccination with BCG, alone or in combination with M. leprae. The tolerant mice developed little or no protection with any of the vaccines, however.

Sensitization or tolerance to Mycobacterium leprae antigen by route of injection.

Aqueous suspensions of heat-killed Mycobacterium leprae in a dose of 10(7) organisms were highly immunogenic when injected intradermally (i.d.). The same dose of bacteria did not sensitize when given intraperitoneally (i.p.) or intravenously (i.v.), and did so only minimally at best when given subcutaneously. The i.d. route was the most immunogenic for sheep erythrocytes also. M. leprae injected i.p. or i.v. stimulated immune tolerance to M. leprae challenge i.d. In older mice (greater than or equal to 8 weeks), the i.v. injections gave more complete tolerance. Mice that had been rendered tolerant by i.v. injections maintained their tolerance for at least 168 days. Prior UV irradiation of intact mice prevented sensitization by the i.d. route. In normal mice, living M. bovis BCG given i.d. produced good sensitization to M. leprae. Mice that had been made tolerant by i.v. injection of M. leprae could be partially sensitized to M. leprae by i.d. immunization with BCG; mixtures of living BCG and heat-killed M. leprae were no more effective than BCG alone. These findings appear to have relevance to the pathogenesis of lepromatous leprosy and its immunoprophylaxis.