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At least 19 recordsLinked to original sources
PubMed2025

Novel mutations associated with clofazimine resistance in Mycobacterium intracellulare.

BACKGROUND: Clofazimine is a promising repurposed drug for treating Mycobacterium avium-intracellulare complex pulmonary disease, but its resistance mechanisms in Mycobacterium intracellulare remain poorly understood. OBJECTIVE: This study aims to elucidate the resistance mechanisms of M. intracellulare to clofazimine. METHODS: We isolated 36 clofazimine-resistant M. intracellulare mutants in vitro and performed whole-genome sequencing to identify resistance-associated mutations. Gene complementation was used to validate the role of the identified mutations. RESULTS: We identified various mutations in the marR gene (WP_009952290.1) in 61% of clofazimine-resistant mutants by whole-genome sequencing. Mutations were identified in additional genes encoding ssuD (flavin-dependent oxidoreductase, C67A), lppI (membrane lipoprotein, C207 deletion), GMC oxidoreductase (glucose-methanol-choline oxidoreductase, G157 deletion), MASE1 domain-containing protein (C62G) and PPE family protein (222C deletion). Gene complementation experiments demonstrated that introducing the wild-type marR in clofazimine-resistant strain (L72) with marR mutations reduced clofazimine MIC from 1 mg/L to susceptible baseline (0.25 mg/L), confirming its critical role in clofazimine resistance. Notably, the M. intracellulare MarR lacks homology to Mycobacterium tuberculosis MarR family protein Rv0678 (MmpR) involved in clofazimine and bedaquiline resistance but is flanked by non-efflux pump genes (dhmA and doxX), and unlike M. tuberculosis, its mutation does not cause bedaquiline cross-resistance, indicating a different MarR and distinct regulatory mechanism for clofazimine resistance in M. intracellulare. CONCLUSIONS: This work highlights marR as a key determinant of clofazimine resistance in M. intracellulare and underscores the need for further mechanistic studies with implications for rapid molecular detection and effective treatment.

Clofazimine↗
PubMedDate not supplied

Clofazimine binding studies with deoxyribonucleic acid.

1. The antileprosy drug, clofazimine, formed stable complexes with DNA and transfer RNA. A quantitative study was made of the spectral red shifts that occurred when clofazimine interacted with DNA. The red shift appeared specific for clofazimine binding to nucleic acid polymers. 2. The degree of clofazimine interaction with DNA was related to the G+C content of the DNA strand. As compared to the human strand, clofazimine interacted with the mycobacterial strand to give a larger red shift which was consistent with the increased G+C content of mycobacterial DNA. 3. It was found that clofazimine interacted with the synthetic single-stranded polynucleotide, poly G, whereas little interaction occurred withpoly A, poly C, or poly U. It was concluded that the guanine base region was a predominant site of clofazimine binding to DNA. 4. No evidence was found to indicate that clofazimine underwent intercalative binding between the base pairs of DNA. 5. It was proposed that clofazimine underwent binding along the minor groove region of DNA at appropriate base sequences which contain guanine. The resultant effect would inhibit template function of the DNA strand.

Binding Sites↗
PubMed1991

Effect of anti-leprosy drugs on superoxide anion production by rat peritoneal macrophage with special reference to light exposed clofazimine.

The present study describes the in vitro effect of anti-leprosy drugs on superoxide anion (O2-) production by rat resident peritoneal macrophages. Of the three drugs tested i.e. clofazimine, rifampicin and dapsone, the first was most effective in increasing O2- production in a dose dependent manner, while rifampicin had some stimulatory effect and dapsone exhibited minimal action. Furthermore, when clofazimine and dapsone were added together it was observed that the increase of O2- production by macrophages due to clofazimine was not significantly altered by the addition of dapsone. Moreover, it was found that killed Mycobacterium leprae could induce a lesser amount of O2- production in comparison to that of Staphylococcus aureus and the enhancement of O2- release due to clofazimine was stimulus dependent. This increase of O2- release after addition of clofazimine was inhibited by the addition of p-bromophenacyl bromide. Another interesting finding was that the enhancement of O2- production by clofazimine gradually decreased as clofazimine was exposed to light for days. On further investigation it was found that ultraviolet, NMR, infrared and mass spectra of the light unexposed and exposed drug were similar, but the diffusion current of the polarogram of light exposed drug was remarkably more than that observed in light unexposed drug, indicating, thereby, a possible increase in the electron accepting capacity of the light reacted molecule. As far as we know this is the first report describing the effect of light exposed clofazimine on the respiratory burst activity of macrophages.

Animals↗
PubMed1991

Mechanisms by which clofazimine and dapsone inhibit the myeloperoxidase system. A possible correlation with their anti-inflammatory properties.

The mechanisms by which two anti-leprotic drugs (clofazimine and dapsone), both with anti-inflammatory properties, inhibit myeloperoxidase (MPO)-catalysed reactions, were investigated. The disappearance of NADH fluorescence was used as an assay for its oxidation. Chloride stimulated the oxidation of NADH in the MPO-H2O2 system in a concentration-dependent manner (50-fold at 150 mM NaCl). Under these conditions Cl- is oxidized and the oxidant formed, presumably hypochlorous acid (HOCl), oxidizes NADH. Observations demonstrating the effect of the drugs on the MPO system, are: (1) Inhibition of Cl(-)-stimulated oxidation of NADH. (2) Inhibition of polypeptide modification in a model protein, thyroglobulin (TG). (3) Protection of MPO against loss of catalytic activity caused by chlorinating oxidants generated by the system. (4) Inhibition of haemoglobin oxidation. Only dapsone was active here. HPLC analyses suggested that the drugs were not significantly metabolized in the MPO-H2O2 system in the absence of Cl-. Bleaching of clofazimine was stimulated by Cl- in the MPO system, suggesting the involvement of HOCl. Clofazimine was found to be a more potent scavenger of HOCl than dapsone when the inhibition of NADH oxidation by reagent HOCl was used as an assay. This finding is also supported by HPLC analyses which indicated a greater sensitivity of HOCl for clofazimine than for dapsone. Relatively low concentrations of dapsone inhibited the oxidation of oxygenated haemoglobin (HbO2), suggesting that the drug was not metabolized to its N-hydroxylated derivative which is thought to be responsible for methaemoglobin (metHb) formation in vivo. It is proposed that the inhibitory mechanism of action of clofazimine is to scavenge chlorinating oxidants generated by the MPO-Cl(-)-H2O2 system, while dapsone converts MPO into its inactive compound II (ferryl) form. The different inhibitory mechanisms of clofazimine and dapsone towards the MPO system may contribute to the anti-inflammatory actions of the drugs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

In vitro, in vivo, and intracellular chemotherapeutic activity of B746, a clofazimine analogue against Mycobacterium avium complex.

B746, an analogue of clofazimine, was compared with the parent compound for its activity against Mycobacterium avium complex (MAC), using several methods. All the studies using simulated in vivo conditions, and those with macrophages from healthy mice or from those treated with these drugs, revealed B746 to be similar to clofazimine. When used alone against experimental MAC infections in beige mice, B746 required an optimal dose of 20 mg/kg. At that dose it proved to be inferior to clofazimine, given at the same dose, but was slightly superior to streptomycin given intramuscularly at 150 mg/kg. On the other hand, in combination with other drugs, it proved to be inferior when given along with either clofazimine or streptomycin. Addition of B746 did not improve the chemotherapeutic efficacy of streptomycin-clofazimine combination in the treatment of established MAC infections of beige mice.

Animals↗
PubMed1976

Clinical trial with clofazimine in leprosy.

This paper summarises our clinical experience with clofazimine in the treatment of 25 cases of reactive states of lepromatous and borderline leprosy and 7 lepromatous patients not responding to dapsone. Corticosteroids, which had to be given for the control of reactions, could be withdrawn and daspone therapy reintroduced during the period of administration of clofazimine. A schedule for the management of moderately severe reactions is recommended. The results of clofazimine treatment were also equally impressive in the group of patients, possibly harbouring dapsone resistant bacilli (in view of their lack of improvement in spite of administration of dapsone under controlled conditions). Clinical regression was associated with a fall in the mean levels of morphological index from 6.8 to 0.5. The need to realise the real indications of this highly useful drug in the treatment of leprosy is stressed.

Adolescent↗
PubMed1976

Quantitative estimation of clofazimine in tissue.

The histological examination and the chemical estimation of clofazimine in the organs removed at autopsy of a patient receiving the drug indicated the accumulation of the drug in the organs of the reticulo-endothelial system and those having a large number of macrophages. The clofazimine levels in the skin from patients receiving the drug and those in whom the drug had been stopped for different periods of time were compared. The skin levels of clofazimine bore a direct relationship to the size of the granuloma. A slow elimination of the drug from the tissues was indicated by the presence of traces of the skin tissue even 1-2 years after stopping the drug. The clinical implication of these findings are discussed.

Adolescent↗
PubMed1992

Role of rifampin and clofazimine ointments in the treatment of leprosy.

The use of rifampin and clofazimine ointments alone and in combination over the patches of tuberculoid patients had a beneficial effect. In combination (rifampin and clofazimine), erythema, inflammation, and edema are considerably reduced. For some of the cases with a recent appearance of a patch, the patch completely disappeared. It is suggested that topical therapy with rifampin and clofazimine ointments would be economical and beneficial in tuberculoid leprosy.

Clofazimine↗
PubMed1992

Clofazimine crystals in alveolar macrophages from a patient with the acquired immunodeficiency syndrome.

An induced sputum specimen from a 35-year-old patient with the acquired immunodeficiency syndrome (AIDS) contained numerous bright orange-red needle-shaped crystal inclusions in his alveolar macrophages. Careful questioning revealed that he recently had been treated for 7 months with clofazimine (200 mg/d) for persistent Mycobacterium avium complex bacteremia. The striking cytologic finding observed is diagnosed easily if the characteristic morphologic appearance of the crystals and their location within the cytoplasm of macrophages and cells of the reticuloendothelial system is appreciated. Although this is the first observation at San Francisco (Calif) General Hospital of clofazimine crystals in a respiratory specimen from a patient with AIDS, the potential of more widespread therapy with clofazimine in patients with AIDS who are infected with M avium complex makes it imperative that the microscopic appearance of these crystals be recognized.

Acquired Immunodeficiency Syndrome↗
PubMed1977

[Pyoderma gangrenosum: Clofazimine therapy].

Two patients with pyoderma gangrenosum have responded remarkably well to treatment with Clofazimine (Lamprène). The first patient, a 68-year old women suffered from pyoderma gangrenosum of the buttock and left leg and on the incision scar for cancer of the breast. Laboratory findings showed monoclonal dysglobulinemia (alpha 2-kappa 2). A daily dose of 300 mg of Clofazimine resulted in complete healing with ten days. The second patient was a 24-year old women suffering from ulcerative colitis and a rapidly progressing pyoderma gangrenosum of the left leg. The lesions was completely healed after two weeks of Clofazimine therapy. The dosage was 200 mg daily and was increased to 400 mg daily. Our cases showed decreased cellular immunity and their phagocytic activity was variable.

Adult↗
PubMedDate not supplied

Long-term clinical toxicity studies with clofazimine (B663) in leprosy.

Fifty-one leprosy patients receiving long-term clofazimine have undergone systematic clinical laboratory testing in a search for any toxicity secondary to the drug. In approximately 220 patient-years of observation and in analyzing approximately 40,000 test results, no statistically significant changes in the direction of abnormality have been observed in SGOT, thymol turbidity, serum globulins, uric acid, alkaline phosphatase, white blood cell count or differential, hematocrit, hemoglobin, BUN, serum creatinine, serum cholesterol, serum albumin, serum potassium, serum calcium, stool for occult blood, routine urinalysis, or reticulocyte count. Statistically significant changes toward abnormality were found in fasting blood sugar and total serum bilirubin. These statistically significant changes in the direction of abnormality were of a small magnitude, were not associated with related clinical signs or symptoms, and do not seem to be of major clinical significance. Despite the accumulation of relatively massive amounts of the drug in various tissues, clofazimine appears remarkably free of serious or life-threatening toxicity clinically. Although the skin and gastrointestinal side effects of clofazimine limit its usefulness, on the evidence to date, its advantages outweigh its disadvantages in those leprosy patients for whom it is indicated.

Adult↗
PubMed2026

Comparative in vitro antimicrobial susceptibility profiles of clofazimine and pyrifazimine against clinical isolates of Mycobacterium tuberculosis in southwest China.

UNLABELLED: Clofazimine (CFZ) is a key drug used to treat drug-resistant tuberculosis (DR-TB), while pyrifazimine (TBI-166) is an improved riminophenazine derivative with better pharmacokinetics. However, there is a lack of data on its susceptibility and resistance in regions with a high disease burden, such as southwestern China. We compared the in vitro antimicrobial activities of CFZ and TBI-166 against 249 DR-TB clinical isolates (99 multidrug-resistant TB [MDR-TB] and 150 pre-extensively drug-resistant TB [pre-XDR-TB] isolates) from southwestern China. TBI-166 exhibited a concentration-dependent biphasic antimicrobial pattern compared to CFZ. TBI-166 showed significantly greater potency at low concentrations (MIC&#x2085;&#x2080; = 0.031 &#xb5;g/mL TBI-166 vs 0.25 &#xb5;g/mL for CFZ; P < 0.001), but attenuated inhibition at high concentrations (MIC&#x2089;&#x2080; > 4 &#xb5;g/mL vs 1 &#xb5;g/mL for CFZ; P < 0.001). However, at high concentrations, the antibacterial effect of TBI-166 is weaker than that of CFZ (40% of TBI-166-resistant isolates have MIC > 4 &#xb5;g/mL, compared to 6.67% of CFZ-resistant isolates, P < 0.001). Epidemiological cutoff values (ECOFFs) were 1.0 &#xb5;g/mL for CFZ and 0.25 &#xb5;g/mL for TBI-166. Based on these in vitro ECOFFs, the resistance rate to TBI-166 (20.1%, 50/249) was significantly higher than that to CFZ (6.0%, 15/249, P < 0.0001). Whole-genome sequencing revealed that mutations in Rv0678 were prevalent in dual-resistant isolates (10/14) and TBI-166 monoresistant isolates (5/40), while Rv1979c mutations were less frequent, and no pepQ mutations were detected. These mutations differed from known hotspots, suggesting potential novel resistance mechanisms. IMPORTANCE: Drug-resistant tuberculosis (DR-TB) remains a major global health challenge, and optimizing treatments for high-burden regions like southwest China is crucial. This study is the first to detail the differential in vitro activities of clofazimine (CFZ) and the novel TBI-166 against clinical DR-TB isolates from southwest China, alongside their resistance-associated genetic profiles. Findings show TBI-166 has enhanced low-concentration potency but higher resistance rates, plus novel mutations in Rv0678 and Rv1979c linked to resistance. These insights will help refine clinical regimens for DR-TB and strengthen regional resistance surveillance, both of which are essential for controlling the spread of DR-TB in southwest China and informing treatment and surveillance strategies in other similar high-burden areas globally.

Clofazimine↗
PubMed1992

In-vivo activity of streptomycin and clofazimine against established infections of Mycobacterium avium complex in beige mice.

Beige mice were challenged with 10(6)-10(7) cfu of Mycobacterium avium intracellulare strain 101 and 22 days later treated with streptomycin 150 mg/kg/day alone, clofazimine 20 mg/kg/day alone, streptomycin 150 mg/kg/day plus clofazimine 20 mg/kg/day, or no antimicrobial agent (untreated controls). Both single-drug therapies partially reduced the cfu counts in spleen, liver and lungs compared with the controls however the combination was significantly more effective and completely eliminated the pathogen from the spleen and lungs of some animals after eight weeks treatment.

Animals↗
PubMed2026

No phenotypic resistance observed for most group-3 and -4 variants in Mycobacterium tuberculosis genes related to bedaquiline, clofazimine, delamanid, and pretomanid in a Central and West African context.

The interpretation of genetic variants' association (or not) with phenotypic resistance to newly introduced and repurposed antituberculosis drugs remains challenging, as many mutations detected by whole-genome sequencing (WGS) are classified as of uncertain significance (group 3) or not associated with resistance-interim (group 4) by the World Health Organization (WHO) mutation catalog v2. We evaluated the phenotypic impact of such variants on minimum inhibitory concentrations (MICs) for bedaquiline (BDQ), clofazimine (CFZ), delamanid (DLM), and pretomanid (PA) in Mycobacterium tuberculosis complex isolates from the multi-country DIAMA cohort in sub-Saharan Africa (SSA), which recruited RR/RS-TB patients na&#xef;ve to these drugs. Among 1,475 isolates with available WGS data, 163 variants met eligibility criteria; due to viable strain unavailability, 89 isolates carrying 29 unique BDQ/CFZ-related and 60 unique DLM/PA-related variants were tested for MIC determination using broth microdilution. Additional structural modeling was performed to explore potential effects of amino-acid substitutions on protein stability. Among BDQ/CFZ-related variants, MICs above the critical concentrations (CCs) were consistently associated with mmpR5 variants, whereas variants in atpE, pepQ, and Rv1979c were not. DLM/PA variants (ddn, fbiA-D, and fgd1) were frequently detected as non-fixed populations, yet rarely yielding MIC values above the CC. Predicted structural destabilization showed no consistent association with MIC values or variant fixation status. Under the conditions tested, phenotypic resistance was not detected for most group 3 and 4 variants detected by WGS. Our data provide evidence from SSA to support improved interpretation of resistance-associated mutations for new and repurposed antituberculosis drugs.IMPORTANCEWhole-genome sequencing increasingly detects Mycobacterium tuberculosis complex mutations classified by the World Health Organization (WHO) mutation catalog v2 as group 3 variants of uncertain significance or group 4 variants not associated with resistance-interim, limiting reliable prediction of resistance to new and repurposed antituberculosis drugs. By generating minimum inhibitory concentration (MIC) data for such variants identified in a multi-country sub-Saharan African cohort, this study provides phenotypic evidence to support future refinement and expansion of the WHO mutation catalog v2. Notably, mmpR5 variants associated with elevated bedaquiline/clofazimine MICs were identified in eight isolates, suggesting that some patients in this cohort may have harbored pre-existing resistance-associated variants yet remained potentially eligible for bedaquiline-containing regimens. These findings contribute to improving the interpretation of genomic resistance data and strengthening surveillance of resistance to bedaquiline, clofazimine, delamanid, and pretomanid.

Mycobacterium tuberculosis↗
PubMed1976

Side effects of clofazimine therapy.

84 patients of leprosy including 15 female patients were treated with Clofzimine on a predetermined dosage regimen. 76 of these were cases of recurrent lepra reaction; 4 cases of proven DDS resistance, 3 of these being complicated by lepra reaction; and 4 were cases of reactional state in Borderline leprosy near the lepromatous end of the spectrum. The common side effect in all cases consisted of red and dark skin pigmentation of varying intensity occuring within 10 weeks of the commencement of therapy. The intensity of the colour was proportionate to the density of the infiltration. Ichthyosis occurred in 66.6% of cases. While the pigmentation was accepted by the patients in general, 10% of the patients considered ichthyosis as stigmatising. While side effects like anorexia, diarrhoea, enlargement of lymph glands and liver, corneal xerosis and loss of weight were self correcting, severe gastrointestinal manifestation, i.e. severe abdominal pain, vomiting and diarrhoea were observed in 9 patients, 5 of whom were females. Mortality was high in the females. On an incidental finding the Isonizair reduced the severity of the manifestations, it was supplemented in 10 cases on Clofazimine therapy and was found to minimise the side effects and the pigmentation due to Clofazimine. Hydration therapy for the ichthyosis and instillation of normal saline and liquid paraffin for corneal xerosis were found to be very useful.

Adolescent↗
PubMed1976

Clofazimine. A new agent for the treatment of pyoderma gangrenosum.

Eight patients had pyoderma gangrenosum. They were given a phendimetrazine tartrate derivative, clofazimine (Lamprene [Britain]), which is a chemotherapeutic agent used mainly in certain mycobacterial infections and which also has phagocytosis-enhancing properties. The effect of this drug was remarkably good, with rapid healing of the lesions commencing 3 to 14 days after treatment was started. The mechanism for the effect of clofazimine in pyoderma gangrenosum is not known.

Adult↗
PubMed1992

A rapid and sensitive high performance liquid chromatographic analysis of clofazimine in plasma.

The high performance liquid chromatographic (HPLC) method of Gidoh, et al. has been modified substantially to provide a simple, rapid, and relatively inexpensive procedure for measuring clofazimine in plasma. The modification involves the use of commonly available laboratory reagents instead of custom-made ones. It also employs a solid phase system for efficient extraction instead of the conventional, less efficient and more labor intensive, liquid-liquid extraction. The inclusion of an internal standard (salicylic acid) improves the precision and reproducibility. It is demonstrated that the method can be used to monitor in vivo clofazimine levels as may be required in formal pharmacokinetic studies or therapeutic drug monitoring.

Animals↗