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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↗
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↗
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↗
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↗
PubMed1979

Treatment of steroid dependant cases of recurrent lepra reaction with a combination of thalidomide and clofazimine.

22 Adult Male Lepromatous patients suffering from recurrent lepra reaction have been allotted to either a regimen of combined treatment with Clofazimine and Thalidomide alone. The initial dosage of either of the drugs was 300 mg daily administered in divided doses of 100 mg three times a day. The preliminary assessment of the ongoing study, indicates that the combined treatment controls the reactional state more rapidly than monotherapy with Thalidomide alone. Results of treatment as regards relief of neuritis and arthritis are particularly gratifying. Four month.ases relapsed into reactional status from 2 days to 15 days. 5 cases on the combined therapy relapsed from one to three months. Three other cases required six months and three cases 8 months treatment before clofazimine could be withdrawn. It would appear that a maintenance therapy of 6 months with flofazimine would be necessary for maintaining the control of reactional episodes while employing this combined therapy.

Adult↗
PubMed1979

Clofazimine in the treatment of pyoderma gangrenosum.

Ten patients with pyoderma gangrenosum, seven female and three male, 25 to 94 years old, mainly with multiple lesions, have been treated with clofazimine, 100 mg three times daily. Associated disease was registered in three patients: diabetes mellitus, a previous adenocarcinoma of the colon treated by hemicolectomy, and pustulosis palmoplantaris. In a further patient, M-component was found in the serum. In seven cases the lesions were completely healed by two to five months of therapy, and in three cases the ulcers healed partially. Side effects were redness of the skin in seven cases and dryness of the skin in two patients. No hematological side effects occurred. The working mechanism is still obscure.

Adult↗
PubMed1975

Clofazimine-enhanced phagocytosis in pustulosis palmaris et plantaris.

The phagocytic ability of neutrophil leucocytes was found to be impaired in patients suffering from pustulosis palmaris et plantaris (PPP). This ability was studied with the aid of the yeast particle method. In 78% of 27 patients whose PPP was in a static phase, the phagocytic function was enhanced, while the PPP abated concomitantly and the pustules disappeared. Impaired phagocytosis and the beneficial effect of clofazimine signify the pathogenic importance of defective neutrophils in PPP.

Acrodermatitis↗
PubMed1978

Antimycobacterial activity of some potential chemotherapeutic compounds.

Fourteen compounds were tested in vitro for activity against Mycobacterium intracellulare and other pathogenic mycobacteria. Only clofazimine and chaulmoogric acid showed significant activity against M. intracellulare. In view of known minimal side effects of clofazimine further studies are warranted for this drug in chemotherapy of M. intracellulare infections.

Clofazimine↗
PubMed2025

Whole genome sequencing-based detection of extensively drug-resistant tuberculosis from Ethiopia.

BACKGROUND: Rapid and accurate detection of extensively drug-resistant tuberculosis is crucial for effective intervention. Next-generation sequencing technologies have been recommended to rapidly and accurately detect resistance to second-line anti-TB drugs. We deployed whole-genome sequencing to detect mutations associated with drug resistance in pre-extensively drug-resistant tuberculosis and extensively drug-resistant tuberculosis strains in Ethiopia. METHODS: This report is part of the routine laboratory-based drug-resistance surveillance in Ethiopia. Among 15 pre-extensively drug-resistant tuberculosis and extensively drug-resistant tuberculosis isolates identified during the study period, eleven isolates were retrieved by Whole-genome sequencing. Illumina NextSeq 550 instruments were used to generate genomic data. Lineage and drug-resistance prediction were performed with Tuberculosis Profiler, while phylogeny was conducted by IQ-tree. RESULTS: Of the genotyped isolates, whole-genome sequencing identifies five extensively drug-resistant tuberculosis and four pre-extensively drug-resistant tuberculosis strains. It detects fluoroquinolone resistance mutations gyrA (Ala90Val, Asp94Tyr, Asp94Gly). Bedaquiline resistance mutations are found in atpE (Glu61Asp) and Rv0678 (139dupG, 141 and 142dupTC). Cross-resistance is identified between bedaquiline and clofazimine (n&#x2009;=&#x2009;4) and delamanid and pretomanid (n&#x2009;=&#x2009;1). Concordance result is observed between phenotypic drug-susceptibility testing and whole-genome sequencing for eight cases, while three cases are discordant (fluoroquinolones, delamanid, and pretomanid). Phylogenetic analysis reveals three major lineages: Lineage 4 (Euro-American, n&#x2009;=&#x2009;6 isolates), Lineage 3 (East African-Indian, n&#x2009;=&#x2009;3 isolates), and Lineage 1 (Indo-Oceanic, n&#x2009;=&#x2009;2 isolates). CONCLUSIONS: Whole-genome sequencing identifies dominant mutations in genes such as gyrA, atpE, and Rv067 that are associated with resistance to second-line anti-tuberculosis drugs. Significant cross-resistance is observed between key second-line drugs, bedaquiline and clofazimine, as well as delamanid and pretomanid. This finding highlights the need for routine genomic surveillance to detect drug resistance early, improve treatment outcomes, and prevent transmission.

Journal Article↗
PubMed2026

Genomic population structure, antimicrobial susceptibility, and clinical features of Mycobacterium xenopi isolates, Frankfurt, Germany, 1995-2020.

Mycobacterium xenopi causes non-tuberculous mycobacterial pulmonary disease (NTM-PD) that is difficult to treat. However, data on the genomic population structure, antimicrobial susceptibility, and the clinical significance of this pathogen remain scarce. We analyzed 76 clinical M. xenopi isolates from 70 patients collected between 1995 and 2020 in Frankfurt am Main, Germany. All isolates underwent phenotypic drug susceptibility testing and whole-genome sequencing. Cluster analysis, including isolates from this study and all hitherto available high-quality M. xenopi genome data sets in the Sequence Read Archive (n = 11), was performed by core genome multilocus sequence typing. In our cohort, only 26.5% of patients met criteria for clinically relevant NTM-PD. Phylogenetic analysis identified three large hospital-associated clusters (&#x2264;10 allelic difference), each involving between 7 and 20 patients and persisting for over 18 years, suggesting prolonged transmission chains or a common environmental source. We also defined three major clades (&#x2264;50 allelic difference), two of which contained isolates from the United Kingdom. Clofazimine and guideline-recommended antimycobacterial agents showed good in vitro efficacy, except rifampicin, with 23.6% resistance. This study represents a major expansion of M. xenopi genomic resources and provides insights into the genomic population structure, phenotypic susceptibility, and clinical characteristics of M. xenopi. Guideline-recommended antimycobacterials show good in vitro activity, while clofazimine may be a valuable addition to M. xenopi therapy. The identified clusters underscore the need for further investigation into transmission dynamics and globally successful clones.IMPORTANCEMycobacterium xenopi is an increasingly recognized opportunistic lung pathogen that is difficult to treat. Infections often occur in patients with pre-existing health conditions and can present substantial diagnostic and therapeutic challenges. A deeper understanding of its genetic diversity and resistance mechanisms is essential for optimal patient management and for clarifying potential transmission routes. By analyzing 76 whole-genome sequences together with detailed clinical information and phenotypic drug-susceptibility data, this study substantially expands the available genomic repertoire for M. xenopi. While clinical relevance was limited in our cohort, most guideline-recommended antimicrobial agents showed good efficacy in vitro. The detection of closely related strains might point toward a common environmental source of infection. These findings highlight the need for continued surveillance and provide a comprehensive foundation that supports more accurate monitoring, improved understanding of disease behavior, and future investigations into M. xenopi pathogenicity.

Humans↗
PubMed2026

A Pilot Study on the Utility of Whole Genome Sequencing for Detecting Drug Resistance in Mycobacterium tuberculosis in the Current Scenario.

PURPOSE: Whole Genome Sequencing (WGS) comprehensively detects all drug-resistant mutants, which can help in the early initiation of specific treatment for the patient. But there is a need to evaluate the performance of WGS in comparison with Line Probe Assays (LPA) and Phenotypic Drug Susceptibility Tests (pDST). METHODS: Consecutive sputum samples (58) found positive for Mycobacterium tuberculosis (MTB) by GeneXpert were tested for first-and second-line LPA, pDST and WGS for anti-tubercular drugs. RESULTS: Of 58, 34 (58.6%) culture isolates were resistant to one or more drugs. Resistance detected by WGS was as follows: Isoniazid 23(39.6%), Rifampicin 21(36.2%), FQs 21(36.2%), Ethambutol 18(31%), Linezolid 12(20.6%), Streptomycin 8(13.8%), Kanamycin 6(10.3%), Amikacin and Capreomycin 5(8.6%), Para-amino salicylic acid 1(1.7%) and Ethionamide 1(1.7%). No resistance was detected to Pyrazinamide, Bedaquiline, Clofazimine, Delamanid and Pretomanid. Lineage 3(EAI) was the most predominant 23(39.6%) followed by Lineage 2: 13(22.4%). Intermediate Resistance (IR) and potential novel mutations were observed in a few cases, CONCLUSION: Overall accuracy for first-line drugs between pDST vs WGS was >98% &pDST vs LPA >95%, while for second-line drugs accuracy was >96% and >90% respectively. IR and potential novel mutations should be followed up closely to understand their clinical significance.

IR↗
PubMed2024

Evaluating culture-free targeted next-generation sequencing for diagnosing drug-resistant tuberculosis: a multicentre clinical study of two end-to-end commercial workflows.

BACKGROUND: Drug-resistant tuberculosis remains a major obstacle in ending the global tuberculosis epidemic. Deployment of molecular tools for comprehensive drug resistance profiling is imperative for successful detection and characterisation of tuberculosis drug resistance. We aimed to assess the diagnostic accuracy of a new class of molecular diagnostics for drug-resistant tuberculosis. METHODS: We conducted a prospective, cross-sectional, multicentre clinical evaluation of the performance of two targeted next-generation sequencing (tNGS) assays for drug-resistant tuberculosis at reference laboratories in three countries (Georgia, India, and South Africa) to assess diagnostic accuracy and index test failure rates. Eligible participants were aged 18 years or older, with molecularly confirmed pulmonary tuberculosis, and at risk for rifampicin-resistant tuberculosis. Sensitivity and specificity for both tNGS index tests (GenoScreen Deeplex Myc-TB and Oxford Nanopore Technologies [ONT] Tuberculosis Drug Resistance Test) were calculated for rifampicin, isoniazid, fluoroquinolones (moxifloxacin, levofloxacin), second line-injectables (amikacin, kanamycin, capreomycin), pyrazinamide, bedaquiline, linezolid, clofazimine, ethambutol, and streptomycin against a composite reference standard of phenotypic drug susceptibility testing and whole-genome sequencing. FINDINGS: Between April 1, 2021, and June 30, 2022, 832 individuals were invited to participate in the study, of whom 720 were included in the final analysis (212, 376, and 132 participants in Georgia, India, and South Africa, respectively). Of 720 clinical sediment samples evaluated, 658 (91%) and 684 (95%) produced complete or partial results on the GenoScreen and ONT tNGS workflows, respectively, with 593 (96%) and 603 (98%) of 616 smear-positive samples producing tNGS sequence data. Both workflows had sensitivities and specificities of more than 95% for rifampicin and isoniazid, and high accuracy for fluoroquinolones (sensitivity approximately &#x2265;94%) and second line-injectables (sensitivity 80%) compared with the composite reference standard. Importantly, these assays also detected mutations associated with resistance to critical new and repurposed drugs (bedaquiline, linezolid) not currently detectable by any other WHO-recommended rapid diagnostics on the market. We note that the current format of assays have low sensitivity (&#x2264;50%) for linezolid and more work on mutations associated with drug resistance is needed. INTERPRETATION: This multicentre evaluation demonstrates that culture-free tNGS can provide accurate sequencing results for detection and characterisation of drug resistance from Mycobacterium tuberculosis clinical sediment samples for timely, comprehensive profiling of drug-resistant tuberculosis. FUNDING: Unitaid.

Humans↗