<i>In Vitro</i> and <i>In Vivo</i> Activities of the Riminophenazine TBI-166 against <i>Mycobacterium tuberculosis</i>

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 <i>Mycobacterium tuberculosis</i> and its potential to accumulate and discolor skin. The <i>in vitro</i> activity of TBI-166 against both drug-sensitive and drug-resistant <i>M.</i><i>tuberculosis</i> 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 <i>M. tuberculosis</i> TBI-166 demonstrates activity at least equivalent to that of CFZ against intracellular <i>M. tuberculosis</i> 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.