PubMed · 8031394
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T Jackson. 1994. Treating Hansen's disease in developing countries.. https://pubmed.ncbi.nlm.nih.gov/8031394/
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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 (MIC₅₀ = 0.031 µg/mL TBI-166 vs 0.25 µg/mL for CFZ; P < 0.001), but attenuated inhibition at high concentrations (MIC₉₀ > 4 µg/mL vs 1 µg/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 µg/mL, compared to 6.67% of CFZ-resistant isolates, P < 0.001). Epidemiological cutoff values (ECOFFs) were 1.0 µg/mL for CFZ and 0.25 µg/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.
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.
Previous studies have shown that when multibacillary leprosy patients were treated with recombinant human interferon gamma (rhuIFN-gamma) for 6-10 months there was an accelerated reduction in the number of acid-fast bacilli in the skin at the site of injection as well as an accelerated bacillary reduction at distal sites. However, this favorable out-come of IFN-gamma treatment was associated with the development of erythema nodosum leprosum (ENL). The present study was undertaken to investigate whether rhuIFN-gamma-induced bacillary clearance could be disassociated from the induction of ENL. rhuIFN-gamma was administered together with thalidomide and conventional multidrug chemotherapy to newly diagnosed leprosy patients. During treatment with this combination of drugs, the mean reduction in bacterial load was the same as the reduction observed with chemotherapy alone. Moreover, the inclusion of thalidomide in the treatment regimen was associated with a low frequency of ENL episodes. A second group of leprosy patients, who had already completed 2 years of chemotherapy, were treated with rhuIFN-gamma only. In those patients who were skin bacilli negative, ENL did not occur during rhuIFN-gamma treatment. In contrast, in bacilli-positive patients the frequency of ENL during rhuIFN-gamma treatment was higher, as was the occurrence of local erythema and induration. However, rhuIFN-gamma treatment without concomitant chemotherapy did not result in a reduction in the bacterial load in the skin of bacilli-positive patients. These findings, taken together, indicate that rhuIFN-gamma does not, by itself, accelerate bacterial clearance, but requires concomitant chemotherapy to achieve the accelerated reduction in bacillary load. Thalidomide reduces the frequency of IFN-gamma-induced ENL, but also eliminates the IFN-gamma-induced bacillary clearance.