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Activity of Clofazimine and TBI-166 against Mycobacterium tuberculosis in Different Administration Intervals in Mouse Tuberculosis Models.

ABSTRACT: Clofazimine (CLO) and TBI-166 belong to the riminophenazine class of antimicrobial agent. TBI-166 exhibited promising antituberculosis activity in vitro and in animal models and is currently under phase I clinical development for the treatment of tuberculosis in China. To identify an optimal dosing regimen to support further clinical development of TBI-166, the efficacies of CLO and TBI-166 were evaluated in two aerosol infection models utilizing BALB/c and C3HeB/FeJNju mice. TBI-166 and CLO were dosed at 20 mg/kg daily for 2 weeks, followed by QD (once daily), TIW (thrice weekly), and BIW (twice weekly) for an additional 10 weeks at the same dose level. The bactericidal activities of TBI-166 and clofazimine via QD, TIW, and BIW dosing regimens were determined after treatment. Once-daily administration of CLO and TBI-166 appeared to be more efficacious than the two intermittent dosing regimens. Once-daily administration of TBI-166 increased the bactericidal activity by approximately 1 log₁₀ CFU in the lung and spleen compared with TIW or BIW dosing after 12 weeks of treatment, while once-daily administration of CLO increased the bactericidal activity by 1.27 to 1.90 log₁₀ CFU/lung and by 1.61 to 2.22 log₁₀ CFU/spleen in the BALB/c mouse model compared to the intermittent therapies. The differences between QD and TIW and between QD and BIW were significant (P < 0.05). The data suggest that accumulated total doses correlate with the log₁₀ CFU reductions. Therefore, intermittent administration of TBI-166 and CLO should be further evaluated at the same accumulated total doses in preclinical and clinical studies.

SUBMITTER: Zhu H

PROVIDER: S-EPMC8097486 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

| S-EPMC6496038 | biostudies-literature

Identifying Regimens Containing TBI-166, a New Drug Candidate against Mycobacterium tuberculosis In Vitro and In Vivo.

Project description:TBI-166, derived from riminophenazine analogues, is under development in a phase I clinical trial in China. TBI-166 showed more potent anti-tuberculosis (anti-TB) activity than did clofazimine in in vitro and animal experiments. To identify potent regimens containing TBI-166 in TB chemotherapy, TBI-166 was assessed for pharmacological interactions in vitro and in vivo with several anti-TB drugs, including isoniazid (INH), rifampin (RFP), bedaquiline (BDQ), pretomanid (PMD), linezolid (LZD), and pyrazinamide (PZA). Using an in vitro checkerboard method, we found that TBI-166 did not show antagonism or synergy with the tested drugs. The interaction relationship between TBI-166 and each drug was indifferent. In in vivo experiments, aerosol infection models with BALB/c and C3HeB/FeJNju mice were established, testing drugs were administered either individually or combined in treatments containing TBI-166 and one, two, or three other drugs, and the bactericidal activities were determined after 4- and 8-week therapeutic treatments. In BALB/c mice, five TBI-166-containing regimens-TBI-166+BDQ, TBI-166+PZA, TBI-166+BDQ+LZD, TBI-166+BDQ+PMD, and TBI-166+BDQ+PMD+LZD-showed significantly more potent efficacy after 4 weeks of treatment compared to the control regimen, INH+RFP+PZA. At the end of an 8-week treatment, lung log CFU counts decreased to undetectable levels in mice treated with each of the five regimens. The rank order of the potency of the five regimens was as follows: TBI-166+BDQ+LZD > TBI-166+BDQ > TBI-166+PZA > TBI-166+BDQ+PMD+LZD > TBI-166+BDQ+PMD. In C3HeB/FeJNju mice, TBI-166+BDQ+LZD was also the most effective of the TBI-166-containing regimens. In conclusion, five potent chemotherapy regimens that included TBI-166 were identified. The TBI-166+BDQ+LZD regimen is recommended for further testing in a TBI-166 phase IIb clinical trial.

| S-EPMC6591646 | biostudies-literature

Identification of novel mutations associated with clofazimine resistance in Mycobacterium tuberculosis.

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| S-EPMC4539095 | biostudies-literature

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Project description:Clofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O2. CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM against M. tuberculosis and found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergistic in vitro with benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was tested in vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains of M. tuberculosis.

| S-EPMC4505229 | biostudies-literature

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Project description:The antileprosy drug clofazimine has shown potential for shortening tuberculosis treatment; however, the current dosing of the drug is not evidence based, and the optimal dosing is unknown. Our objective was to conduct a preclinical evaluation of the pharmacokinetics and pharmacodynamics of clofazimine in the mouse model of tuberculosis, with the goal of providing useful information on dosing for future studies. Pharmacokinetic parameters were evaluated in infected and uninfected BALB/c mice. Pharmacodynamic parameters were evaluated in Mycobacterium tuberculosis-infected mice that were treated for 12 weeks with one of six different clofazimine dosing regimens, i.e., doses of 6.25, 12.5, and 25 mg/kg of body weight/day and 3 regimens with loading doses. Clofazimine progressively accumulated in the lungs, livers, and spleens of the mice, reaching levels of greater than 50 μg/g in all tissues by 4 weeks of administration, while serum drug levels remained low at 1 to 2 μg/ml. Elimination of clofazimine was extremely slow, and the half-life was dependent on the duration of drug administration. Clofazimine exhibited dose-dependent tissue and serum concentrations. At any dose, clofazimine did not have bactericidal activity during the first 2 weeks of administration but subsequently demonstrated potent, dose-independent bactericidal activity. The antituberculosis activity of clofazimine was dependent on neither the dose administered nor the drug concentrations in the tissues, suggesting that much lower doses could be effectively used for tuberculosis treatment.

| S-EPMC4432183 | biostudies-literature

Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis.

Project description:BackgroundDrug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by off-target resistance-associated variants (RAVs) in the mmpR5 gene (Rv0678), the regulator of an efflux pump, which can also confer cross-resistance to clofazimine, another TB drug.MethodsWe compiled a dataset of 3682 Mtb genomes, including 180 carrying variants in mmpR5, and its immediate background (i.e. mmpR5 promoter and adjacent mmpL5 gene), that have been associated to borderline (henceforth intermediate) or confirmed resistance to bedaquiline. We characterised the occurrence of all nonsynonymous mutations in mmpR5 in this dataset and estimated, using time-resolved phylogenetic methods, the age of their emergence.ResultsWe identified eight cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic reconstruction points to multiple emergence events and circulation of RAVs in mmpR5, some estimated to predate the introduction of bedaquiline. However, epistatic interactions can complicate bedaquiline drug-susceptibility prediction from genetic sequence data. Indeed, in one clade, Ile67fs (a RAV when considered in isolation) was estimated to have emerged prior to the antibiotic era, together with a resistance reverting mmpL5 mutation.ConclusionsThe presence of a pre-existing reservoir of Mtb strains carrying bedaquiline RAVs prior to its clinical use augments the need for rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.

| S-EPMC10877763 | biostudies-literature

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Project description:Antibiotic resistance among bacterial pathogens poses a major global health threat. Mycobacterium tuberculosis complex (MTBC) is estimated to have the highest resistance rates of any pathogen globally. Given the low growth rate and the need for a biosafety level 3 laboratory, the only realistic avenue to scale up drug susceptibility testing (DST) for this pathogen is to rely on genotypic techniques. This raises the fundamental question of whether a mutation is a reliable surrogate for phenotypic resistance or whether the presence of a second mutation can completely counteract its effect, resulting in major diagnostic errors (i.e., systematic false resistance results). To date, such epistatic interactions have only been reported for streptomycin that is now rarely used. By analyzing more than 31,000 MTBC genomes, we demonstrated that the eis C-14T promoter mutation, which is interrogated by several genotypic DST assays endorsed by the World Health Organization, cannot confer resistance to amikacin and kanamycin if it coincides with loss-of-function (LoF) mutations in the coding region of eis. To our knowledge, this represents the first definitive example of antibiotic reversion in MTBC. Moreover, we raise the possibility that mmpR (Rv0678) mutations are not valid markers of resistance to bedaquiline and clofazimine if these coincide with an LoF mutation in the efflux pump encoded by mmpS5 (Rv0677c) and mmpL5 (Rv0676c).

| S-EPMC8522733 | biostudies-literature

Mutations in pepQ Confer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis.

Project description:The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, ≥4-fold upward shifts in bedaquiline MIC during treatment have been attributed to non-target-based mutations in Rv0678 that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level clofazimine resistance, presumably by a similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and clofazimine cross-resistance in Mycobacterium tuberculosis: loss-of-function mutations in pepQ (Rv2535c), which corresponds to a putative Xaa-Pro aminopeptidase. pepQ mutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without clofazimine, and were shown to have bedaquiline and clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression of Rv0678, mmpS5, or mmpL5 between mutant and parent strains. Complementation of a pepQ mutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility both in vitro and in mice. Although the mechanism by which mutations in pepQ confer bedaquiline and clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene.

| S-EPMC4958187 | biostudies-literature

Treatment-Shortening Effect of a Novel Regimen Combining Clofazimine and High-Dose Rifapentine in Pathologically Distinct Mouse Models of Tuberculosis.

Project description:Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and clofazimine in clinical trials.

| S-EPMC6535519 | biostudies-literature

Investigation of Clofazimine Resistance and Genetic Mutations in Drug-Resistant <i>Mycobacterium tuberculosis</i> Isolates.

Project description:Recently, as clofazimine (CFZ) showed a good therapeutic effect in treating multi-drug-resistant tuberculosis (MDR-TB), the anti-tuberculosis activity and resistance were re-focused. Here, we investigated the CFZ resistance and genetic mutations of drug-resistant Mycobacterium tuberculosis (DR-Mtb) isolates to improve the diagnosis and treatment of drug-resistant TB patients. The minimal inhibitory concentration (MIC) of CFZ was examined by resazurin microtiter assay (REMA) with two reference strains and 122 clinical isolates from Korea. The cause of CFZ resistance was investigated in relation to the therapeutic history of patients. Mutations of Rv0678, Rv1979c and pepQ of CFZ resistant isolates were analyzed by PCR and DNA sequencing. The rate of CFZ resistance with MIC > 1 mg/L was 4.1% in drug-resistant Mtb isolates. The cause of CFZ resistance was not related to treatment with CFZ or bedaquiline. A CFZ susceptibility test should be conducted regardless of dugs use history. The four novel mutation sites were identified in the Rv0678 and pepQ genes related to CFZ resistance in this study.

| S-EPMC9000149 | biostudies-literature

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