In our efforts to develop new drugs for the treatment of tuberculosis, especially that caused by multidrug-resistant strains, we investigated clofazimine (CFM) and two of its analogs, B4154 and B4157, for their antituberculosis activities. Twenty M. tuberculosis strains were tested, including 16 drug-resistant strains (strains resistant to one or more antituberculosis drugs), for their susceptibilities to these three agents. All of the strains were found to be susceptible to B4154 and B4157, and one strain showed moderate resistance to CFM. The MICs of B4154, B4157, and CFM at which 90% of strains were inhibited were 0.25, 0.12, and < or = 1.0 microgram/ml, respectively. The intracellular activities of CFM and B4157 were superior to that of B4154. The chemotherapeutic activities of the three compounds were evaluated in C57BL/6 mice. At a dose of 20 mg/kg of body weight, the activity of CFM was slightly superior to that of B4157; however, both compounds prevented mortality and caused a significant reduction in the numbers of CFU in the lungs and spleens. The animals treated with B4157 showed less pigmentation than animals treated with CFM. The chemotherapeutic activity of CFM was comparable to those of rifampin and isoniazid. Complete susceptibility of multidrug-resistant strains to CFM and B4157 and the therapeutic efficacies of these compounds against mouse tuberculosis make these drugs attractive agents for the treatment of drug-resistant tuberculosis.

Antituberculosis activity of clarithromycin (CLA), a macrolide antibiotic, was investigated in vitro, in macrophages, and in C57BL/6 mice. CLA showed high in vitro MICs (4 to > 16 g/ml) for several strains of Mycobacterium tuberculosis and caused slight enhancement of activity of rifampin (RIF) against H37Rv but failed to increase the activity of either RIF or isoniazid (INH) against other strains. However, inside J774A.1 macrophages, CLA showed high activity and was synergistic with RIF against some strains of tubercle bacilli susceptible or resistant to INH and RIF. In the in vivo studies with a drug-susceptible strain (H37Rv), CLA protected mice from mortality due to tuberculosis for up to 8 weeks of observation. The CFU data for lungs and spleens revealed that the antituberculosis activity of CLA is inferior to those of INH and streptomycin. However, the activity of CLA when used alone or in combination was comparable to that of thiacetazone, indicating its potential usefulness as a secondary drug for the treatment of tuberculosis.Recent outbreaks of tuberculosis with multiple-drug-resistant (MDR) tubercle bacilli have indicated an urgent need for new drugs. New methods of establishing the antimycobacterial properties of the available drugs to the maximum extent are also being pursued. In this endeavor, enhancement of the susceptibility of the MDR bacilli to some drugs to which they were originally resistant has been investigated by us and others (1-3, 12, 15). Clarithromycin (CLA), a recently introduced macrolide antibiotic, was shown to have in vitro synergistic activity with isoniazid (INH), ethambutol, and rifampin (RIF) against MDR strains of tubercle bacilli (1, 3). This finding is interesting, since individually none of these drugs, including CLA, is active against such organisms. In fact, CLA, which is used for Mycobacterium avium complex (MAC) disease (4-6), has not been used for treatment of Mycobacterium tuberculosis because of its high MIC.We have investigated the activity of CLA alone and in combination with INH and RIF against drug-susceptible and MDR tubercle bacilli. Besides extending the findings of earlier reports (1, 3) to more-detailed studies using the radiometric (BACTEC) technique and assessing synergism by quantitative methods, our studies involved assessments of the activity of CLA by itself and in combination against drug-susceptible and MDR strains of tubercle bacilli in the macrophage model and against drug-susceptible M. tuberculosis H37Rv infections in C57BL/6 mice. MATERIALS AND METHODSMycobacterial strains. The M. tuberculosis strains used in this study consisted of two drug-susceptible strains, including H37Rv, and seven MDR isolates obtained from Centers for Disease Control and Prevention, Atlanta, Ga., and University of Illinois Hospital, Chicago. The organisms were grown in Middlebrook 7H9 broth, and the bacilli in log-phase growth were washed twice with Hanks' balanced salt solution (HBSS) and adjusted to a McFarland no. 1 standard.Drugs. CLA was obtained from Abbott Lab...

The antimycobacterial activities of a new rifampin (RIF) derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (T9), against 20 susceptible and multidrug-resistant strains of Mycobacterium tuberculosis and 20 Mycobacterium avium complex (MAC) strains were investigated. The radiometric MICs of T9 for M. tuberculosis were significantly lower than those of RIF. The MICs of T9 and RIF at which 90% of the RIF-susceptible strains were inhibited were <0.25 and <0.5 g/ml, respectively. Interestingly, T9 had lower MICs against some RIF-resistant M. tuberculosis strains. T9 had better activity against MAC strains, and the MIC at which 90% of the MAC strains were inhibited was <0.125 g/ml, and that of RIF was <2.0 g/ml. T9 also showed high in vitro bactericidal and intracellular activities which were significantly superior to those of RIF against both M. tuberculosis and MAC strains. More importantly, T9 showed excellent in vivo activity against M. tuberculosis H37Rv compared with that of RIF in both the lungs and spleens of C57BL/6 mice, indicating the potential therapeutic value of T9 in the treatment of mycobacterial infections.In recent years, several rifamycin derivatives (including rifapentine, rifabutin, and KRM-1648, etc.) have been investigated for their activities against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) in in vitro, macrophage, and animal models (1,3,8,10). In a similar attempt, the Chemical Pharmaceutical Research Institute, Sofia, Bulgaria, has developed a new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV, which was called T9 (Fig. 1). Investigations conducted by the developers of the drug have indicated good therapeutic activity, lack of toxicity, and favorable pharmacokinetics and bioavailability in experimental animals (4, 5). In this communication we report the antimycobacterial activities of T9 against M. tuberculosis and MAC. MATERIALS AND METHODSDrugs. T9 was supplied by the Chemical Pharmaceutical Research Institute (NIHFI); rifampin (RIF) was purchased from Sigma Chemical Company (St. Louis, Mo.). For in vitro studies, stock solutions of the drugs were prepared in dimethyl sulfoxide and stored at Ϫ80ЊC. Required dilutions were made in distilled water for inoculation to BACTEC vials and for macrophage studies. For in vivo studies, the drugs were suspended in sterile distilled water containing 0.5% carboxymethyl cellulose. Drug suspensions were made every week and stored at Ϫ10ЊC until use.Mycobacteria. M. tuberculosis strains used in the study consisted of susceptible and multidrug-resistant (MDR) strains of M. tuberculosis. The sources of the strains and detailed drug susceptibility patterns have been described previously (8). M. avium strains used in the study were smooth, transparent colonial forms isolated from AIDS patients.Macrophages. Intracellular activity of T9 was determined with the J774A.1 mouse macrophage cell line, which was obtained from the American Type Culture Collection and maintained in Dulbecco's modified Eagle's m...

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