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

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.

SUBMITTER: Xu J

PROVIDER: S-EPMC6496038 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Xu Jian J Wang Bin B Fu Lei L Zhu Hui H Guo Shaochen S Huang Haihong H Yin Dali D Zhang Ye Y Lu Yu Y

Antimicrobial agents and chemotherapy 20190425 5

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 evaluate ...[more]

PMID: 30782992

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Project description:Multidrug-resistant tuberculosis (MDR-TB) is often associated with poor clinical outcomes. In this study, we evaluated the potential of nosiheptide (NOS) as a new drug candidate for treating Mycobacterium tuberculosis infections, including MDR-TB. The antimicrobial susceptibility testing was performed to determine the MICs of NOS against 18 reference strains of slowly growing mycobacteria (SGM) and 128 clinical isolates of M. tuberculosis. The postantibiotic effects (PAE) and interaction with other antituberculosis drugs of NOS were also evaluated using M. tuberculosis H37Rv. Fifteen out of the 18 tested reference strains of SGM had MICs far below 1 μg/mL. From the 128 M. tuberculosis clinical isolates, the MIC50 and MIC90 were 0.25 μg/mL and 1 μg/mL, respectively; the tentative epidemiological cutoff (ECOFF) was defined at 1 μg/mL. Furthermore, a Lys89Thr mutation was found in one M. tuberculosis isolate with a MIC of NOS >8 μg/mL. After 24 h of incubation, NOS at 1 μg/mL inhibited 25.79 ± 1.22% of intracellular bacterial growth, which was comparable with the inhibitory rate of 25.71 ± 3.67% achieved by rifampin at 2 μg/mL. Compared to rifampicin and isoniazid (INH), NOS had a much longer PAE, i.e., a value of about 16 days. In addition, a partial synergy between NOS and INH was observed. NOS has potent inhibitory activities against M. tuberculosis in vitro as well as in macrophages. Furthermore, the long PAE and partial synergistic effect with INH, in addition to the added safety of long-term use as a feed additive in husbandry, provide support for NOS being a promising drug candidate for tuberculosis treatment. IMPORTANCE This study is aimed at chemotherapy for MDR-TB, mainly to explore the anti-TB activity of the existing chemotherapeutic reagent. We found that NOS has potent inhibitory activities against M. tuberculosis in vitro regardless of the drug-resistant profile. Furthermore, NOS also showed the long PAE and partial synergistic effect with INH and is nontoxic, providing support for its promise as a drug candidate for drug-resistant tuberculosis treatment.

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

Publications

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

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