Chemotherapeutic activity of benzoxazinorifamycin, KRM-1648, against Mycobacterium tuberculosis in C57BL/6 mice

In Vitro and In Vivo Activities of New Rifamycin Derivatives Against Mycobacterial Infections

“…In the second experiment (established infection protocol), mice were infected intravenously with 5.8 x 10 5 CFU of H37Rv strain of M. tuberculosis and treated 2 weeks later with 20 mg/kg of RIF, RFB or RLZ five days a week for 8 weeks. The results of this experiment showed that 8 weeks of treatment with RFB was able to sterilize the spleens of 4 of 5 mice, however, 8 weeks of treatment with RIF was only able to sterilize the spleen of 1 of 5 mice [5].…”

“…When mice are treated for 35 days with 2.5 mg/kg RIF, RFB, RPT or RLZ, CFU are above zero but are much smaller in RLZ, RPT and RFB treated groups than in the RIF treated group [4]. In another study reported by Reddy et al [5], 2 experiments were performed. In the first one (early treatment protocol), the mice were infected intravenously with 10 7 CFU of H37Rv strain of M. tuberculosis and treated the day after infection with 20 mg/kg of RIF, RFB or RLZ five days a week for 12 weeks.…”

“…In the spleens, after 6 weeks without treatment, 3 mice had CFU and after 16 weeks without treatment 3 of 4 mice had CFU. The RIF treatment was not able to render neither spleen nor lungs culture negative after 12 weeks of treatment [5]. In the second experiment (established infection protocol), mice were infected intravenously with 5.8 x 10 5 CFU of H37Rv strain of M. tuberculosis and treated 2 weeks later with 20 mg/kg of RIF, RFB or RLZ five days a week for 8 weeks.…”

Prospects for development of new antimycobacterial drugs

“…87,121,[131][132][133][134][135][136][137][138] KRM had much greater in-vivo therapeutic efficacy than RFP and RBT against MTB infection induced in mice. 121,[133][134][135][136] Although clinical isolates of MTB exhibited cross-resistance to KRM and either RFP or RBT, KRM still exhibited significantly stronger in-vivo activity against moderately RFP-resistant MTB strains than did RFP. 121 KRM may therefore be useful for the clinical treatment of patients with MTB infection caused by strains with moderate levels of RFP resistance.…”

“…122 However, the MICs of KRM against intramacrophage MTB were comparable to its MICs against extracellular MTB. 122,129 It thus appears 14 , , , Hirata (1995) Luna-Herrera (1995), Moghazeh (1996), Mor (1996), Dhople (1997) Suzuki (1997), In-vivo activity against mycobacterial infections induced in mice and rabbits Tomioka (1992,1997), Emori (1993Emori ( , 1998, Bermudez (1994) Klemens ( , 1996, Hirata (1995), Reddy (1996), , Lenaerts (1999), , that, after the uptake of KRM by macrophages, only a portion of the drug was delivered to MTB organisms replicating within macrophages. It should also be noted that the activity of KRM against intramacrophage MTB was greatly decreased when RFP-resistant strains were used as target organisms.…”