ABSTRACT
Twenty-five compounds structurally related to clofazimine were tested for their ability to inhibit the growth of Mycobacterium leprae using the kinetic method of drug evaluation in the mouse foot pad model of leprosy. Seven of the phenazine derivatives displayed anti-M. leprae activity comparable to that of clofazimine when administered at a concentration of 0.01% (w/w) in the diet. Three of the compounds, B746, B4087, and B4101, were active when administered at 0.001% in the diet. At a dietary concentration of 0.0001%, B4087 and B4101 were slightly more active than clofazimine, while B746 was less active. In the kinetic method of drug evaluation, greater anti-M. leprae activity of phenazine derivatives was generally associated with greater pigmentation of abdominal fat. Of the compounds which did not cause pigmentation when fed at a concentration of 0.01% in the diet B4090 was the most active. This compound also inhibits the growth of a clofazimine-resistant M. smegmatis strain.
Subject(s)
Leprosy/drug therapy , Mycobacterium leprae/drug effects , Phenazines/pharmacology , Abdomen , Adipose Tissue/drug effects , Animals , Clofazimine/chemistry , Clofazimine/pharmacology , Clofazimine/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Kinetics , Leprosy/microbiology , Mice , Molecular Structure , Mycobacterium leprae/growth & development , Phenazines/chemistry , Phenazines/therapeutic use , PigmentationABSTRACT
The anti-Mycobacterium leprae activity of clarithromycin when administered alone and in combination with rifampin and dapsone in the diet was determined using the kinetic method of drug evaluation in mice. Clarithromycin when administered at a concentration of 0.1% (w/w) in the diet completely prevented growth of 2 pan-susceptible, 3 dapsone-resistant, 2 rifampin-resistant, and 2 rifampin and dapsone double resistant strains of M. leprae. A 0.03% (w/w) concentration also completely prevented growth of M. leprae in all mice infected with 2 of 7 strains tested, but in only some of the mice infected with the remaining 5 strains. No antagonistic drug interactions were observed between clarithromycin and dapsone or rifampin. The addition of clarithromycin to the currently recommended multidrug regimen should improve the rate of killing of M. leprae and help to prevent the growth of dapsone-resistant and rifampin-resistant strains.
Subject(s)
Clarithromycin/pharmacology , Dapsone/pharmacology , Mycobacterium leprae/drug effects , Rifampin/pharmacology , Administration, Oral , Animals , Clarithromycin/administration & dosage , Clarithromycin/therapeutic use , Dapsone/administration & dosage , Dapsone/therapeutic use , Drug Interactions , Drug Resistance, Microbial , Female , Leprosy/drug therapy , Mice , Rifampin/administration & dosage , Rifampin/therapeutic useSubject(s)
Bacterial Proteins/genetics , Base Sequence , Escherichia coli/genetics , Heat-Shock Proteins/genetics , Mycobacterium tuberculosis/genetics , Sequence Homology, Nucleic Acid , Amino Acid Sequence , Antigens, Bacterial/genetics , Antigens, Bacterial/isolation & purification , Bacterial Proteins/isolation & purification , Chaperonin 10 , Molecular Sequence Data , Mycobacterium tuberculosis/immunologyABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Mycobacterium leprae/drug effects , Animals , Cefoxitin/pharmacology , Cefuroxime/pharmacology , Cephalosporins/pharmacology , Female , Leprosy/drug therapy , Leprosy/microbiology , Mezlocillin/pharmacology , Mice , Mycobacterium leprae/growth & development , Penicillins/pharmacologySubject(s)
Leprostatic Agents/pharmacology , Mycobacterium leprae/drug effects , Animals , Cycloserine/analogs & derivatives , Drug Combinations/pharmacology , Drug Evaluation, Preclinical , Ethambutol/pharmacology , Ethionamide/analogs & derivatives , Isoniazid/analogs & derivatives , Isoniazid/pharmacology , Mice , Prothionamide/analogs & derivatives , Structure-Activity Relationship , Sulfones/pharmacology , Thiosemicarbazones/pharmacologyABSTRACT
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.
Subject(s)
BCG Vaccine/immunology , Bacterial Vaccines/immunology , Immune Tolerance , Leprosy/immunology , Mycobacterium leprae/immunology , Animals , Dose-Response Relationship, Immunologic , Female , Mice , VaccinationABSTRACT
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.
Subject(s)
Hypersensitivity, Delayed , Immune Tolerance , Immunization , Mycobacterium leprae/immunology , Animals , BCG Vaccine/immunology , Female , Injections, Intradermal , Injections, Intraperitoneal , Injections, Intravenous , Injections, Subcutaneous , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Ultraviolet RaysABSTRACT
Viable suspensions of BCG, an attenuated strain of Mycobacterium bovis, have been previously shown to immunize mice against infections with M. leprae. Usually, the mice have been vaccinated about 1 month before challenge. Experiments have now been carried out with single intradermal injections of BCG given before or after the M. leprae challenge. Approximately equal immunizing effect was seen in one experiment when the BCG was given at -168, -119, -70, and -28 days relative to challenge. Approximately equal protection was observed in another experiment when the vaccine was given at -28, +28, and +56 days. In the latter experiment, however, vaccine given at +91 days appeared to be somewhat less effective. Enlargement of the lymph nodes regional to the intradermal vaccine site persisted for at least the duration of the experiment, approximately 400 days. Thus, antigenic stimulation appears to have continued throughout the period of observation.