In Vitro and In Vivo Activities of the Riminophenazine TBI-166 against Mycobacterium tuberculosis.
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| Abstract |
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 × 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 low-dose 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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| Authors | Jian Xu, Bin Wang, Lei Fu, Hui Zhu, Shaochen Guo, Haihong Huang, Dali Yin, Ye Zhang, Yu Lu |
| Journal | Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 63 Issue 5 (05 2019) ISSN: 1098-6596 [Electronic] United States |
| PMID | 30782992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2019 American Society for Microbiology. |
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