Section 67
Chapter 66,513

In Vitro and in Vivo Activities of the Riminophenazine TBI-166 against Mycobacterium tuberculosis

Xu, J.; Wang, B.; Fu, L.; Zhu, H.; Guo, S.; Huang, H.; Yin, D.; Zhang, Y.; Lu, Y.

Antimicrobial Agents and ChemoTherapy 63(5)


ISSN/ISBN: 1098-6596
PMID: 30782992
DOI: 10.1128/aac.02155-18
Accession: 066512158

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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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