期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 63, 期 5, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.02155-18
关键词
riminophenazine; TBI-166; clofazimine; in vivo; Mycobacterium tuberculosis
资金
- National Science and Technology Project of China [2015ZX09102007-015]
- National Natural Science Foundation of China [81803588]
- Global Alliance for TB Drug Development [81803588]
The riminophenazine agent clofazimine (CFZ) is repurposed as an important component of the new short-course multidrug-resistant tuberculosis regimen and significantly shortens first-line regimen for drug-susceptible tuberculosis in mice. However, CFZ use is hampered by its unwelcome skin discoloration in patients. A new riminophenazine analog, TBI-166, was selected as a potential next-generation antituberculosis riminophenazine following an extensive medicinal chemistry effort. Here, we evaluated the activity of TBI-166 against Mycobacterium tuberculosis and its potential to accumulate and discolor skin. The in vitro activity of TBI-166 against both drug-sensitive and drug-resistant M. tuberculosis is more potent than that of CFZ. Spontaneous mutants resistant to TBI-166 were found at a frequency of 2.3 x 10(-7) in wild strains of M. tuberculosis. TBI-166 demonstrates activity at least equivalent to that of CFZ against intracellular M. tuberculosis and in lowdose aerosol infection models of acute and chronic murine tuberculosis. Most importantly, TBI-166 causes less skin discoloration than does CFZ despite its higher tissue accumulation. The efficacy of TBI-166, along with its decreased skin pigmentation, warrants further study and potential clinical use.
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