Deciphering the late steps of rifamycin biosynthesis
Feifei QiChao LeiFengwei LiXingwang ZhangJin WangWei ZhangZhen FanWeichao LiGong‐Li TangYouli XiaoGuoping ZhaoShengying Li
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Abstract Rifamycin-derived drugs, including rifampin, rifabutin, rifapentine, and rifaximin, have long been used as first-line therapies for the treatment of tuberculosis and other deadly infections. However, the late steps leading to the biosynthesis of the industrially important rifamycin SV and B remain largely unknown. Here, we characterize a network of reactions underlying the biosynthesis of rifamycin SV, S, L, O, and B. The two-subunit transketolase Rif15 and the cytochrome P450 enzyme Rif16 are found to mediate, respectively, a unique C–O bond formation in rifamycin L and an atypical P450 ester-to-ether transformation from rifamycin L to B. Both reactions showcase interesting chemistries for these two widespread and well-studied enzyme families.Keywords:
Rifamycin
Rifapentine
Rifabutin
Rifaximin
The dose-response activity of rifabutin and the comparative activities of rifabutin and rifapentine were evaluated in the beige mouse model of disseminated Mycobacterium avium complex (MAC) infection. In the dose-response study, mice were infected intravenously with approximately 10(7) viable M. avium ATCC 49601. Treatment with rifabutin at 10, 20, or 40 mg/kg of body weight was started 7 days postinfection and was administered daily for 10 days. The mice were sacrificed 3 to 5 days after the last dose. Spleens, livers, and lungs were homogenized, and viable cell counts were determined by serial dilution and plating onto Middlebrook 7H10 agar. A dose-related reduction in MAC cell counts in the organs was noted for this MAC isolate. The comparative activities of rifabutin and rifapentine were determined against a total of five MAC isolates in the beige mouse model. Rifabutin or rifapentine (20 mg/kg each) was administered to infected mice for 10 days. Groups of treated mice were compared with untreated control animals. Despite favorable in vitro susceptibility results, rifabutin and rifapentine had activities in the spleens against only two of the five MAC isolates. For these two MAC isolates, rifabutin was more active than rifapentine. These agents had activities in the lungs against three of five isolates. Further study of rifabutin or rifapentine against a broader range of clinical isolates in a murine infection model may be useful as part of the continuing development of newer rifamycins as anti-MAC agents.
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Rifamycin
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SUMMARY The activities of the rlfamyclns, rlfabutln, FCE 22807, rlfapentlne, and rlfampln, were studied within unstimulated peritoneal macrophages infected with Mycobacterium mlcroti and In cultures of M. mlcroti and M. tuberculosis In 7H·9 medium without Tween 80. In macrophage cul tures, serial rifamycin concentrations were added after a 2.5 h phagocytosis period, and viable counts were doneafter Incubation for 5 to 6 days. Toensure comparability with the dally drug replacements in the macrophage experiments, the period of exposure to serial rifamycin concentrations In 7H·9 medium was kept to only 3 days. The MICs of M. mlcroti and M. tuberculosis were similar. The MICs of rifabutln and FCE 22807 were 2.5 times lower and that of rlfapentlne 1.7 times lower than the MIC of rlfampln. None of the rlfamyclns were concentrated In macrophages, the MICs being higher In the macrophagesthan In vitro by a factor of 2·fold for rlfabutin, 6.7·fold for rlfampin, 20·fold for FCE 22807, and 26·fold for rlfapentine.
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Rifabutin and Rifapentine Compared with Rifampin againstMycobacterium leprae in MiceIn recent years, new derivatives of rifamide have been developed and tested, particularly rifabutin (RBU) (9) and rifapentine (RPE) (1), which are active on Mycobacterium tuberculosis and other medically important mycobacteria (1, 4, 13, 14).We studied their activity against Mycobacterium
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The activities of the rifamycins, rifabutin, FCE 22807, rifapentine, and rifampin, were studied within unstimulated peritoneal macrophages infected with Mycobacterium microti and in cultures of M. microti and M. tuberculosis in 7H-9 medium without Tween 80. In macrophage cultures, serial rifamycin concentrations were added after a 2.5 h phagocytosis period, and viable counts were done after incubation for 5 to 6 days. To ensure comparability with the daily drug replacements in the macrophage experiments, the period of exposure to serial rifamycin concentrations in 7H-9 medium was kept to only 3 days. The MICs of M. microti and M. tuberculosis were similar. The MICs of rifabutin and FCE 22807 were 2.5 times lower and that of rifapentine 1.7 times lower than the MIC of rifampin. None of the rifamycins were concentrated in macrophages, the MICs being higher in the macrophages than in vitro by a factor of 2-fold for rifabutin, 6.7-fold for rifampin, 20-fold for FCE 22807, and 26-fold for rifapentine.
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Rifamycins are integral part of the combination regimen for treatment of pulmonary Mycobacterium avium-complex [MAC] infection, but different practitioners prefer different rifamycins. The objective of the study was to compare microbial kill and resistance emergence of rifamycins using principles of pharmacokinetics/pharmacodynamics. First, we identified rifamycin MICs in 20 MAC isolates from patients followed by concentration-response studies in test-tubes. Next, we examined efficacy and resistance suppression of three doses of each rifamycin in the hollow fiber system model of pulmonary MAC [HFS-MAC], mimicking human like concentration-time profile of the drugs. HFS-MAC units were repetitively sampled for total and drug-resistant MAC burden and for drug concentration measurements. Inhibitory sigmoid E max model, linear regression, and analysis of variance was used for data analysis. For rifabutin 90% of isolates had MIC ≤ 0.125 mg/L while for both rifampin and rifapentine this was ≤2.0 mg/L. There was no statistically significant difference ( p > 0.05) in maximal kill and effective concentration mediating 50% of the bacterial kill among three rifamycins in the static concentration experiment. In the HFS-MAC, the bactericidal kill (day 0–4) for rifampin was 0.89 (95% Confidence Interval (CI): 0.43–1.35), for rifapentine was 1.05 (95% CI: 0.08–1.23), and for rifabutin was 0.92 (95% CI: 0.61–1.24) log 10 CFU/ml, respectively. Rifamycins monotherapy failed after just 4-days of treatment and entire MAC population was drug resistant on day 26 of the study. There was no dose dependent difference in MAC kill or resistance suppression among the three rifamycins tested in the HFS-MAC. Therefore, replacing one rifamycin, due to emergence of drug-resistance, with other may not be beneficial in clinical setting.
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The comparative activities of newer rifamycin analogs and the activity of rifabutin or rifapentine in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J; bgj/bgj) mouse model of disseminated Mycobacterium avium infection. Rifabutin and rifapentine at 20 mg/kg of body weight had comparable activities. P/DEA and CGP 7040 at 20 mg/kg were less active. The combination of ethambutol at 125 mg/kg and rifabutin at 20 mg/kg resulted in a slight increase in activity beyond that seen with rifabutin alone against organisms in the spleens. The combination of ethambutol and rifapentine at 20 mg/kg resulted in a modest increase in activity beyond that seen with rifapentine alone against organisms in the lungs. The combination of ethionamide at 125 mg/kg and rifapentine resulted in a decrease in activity compared with that for rifapentine alone. The combination of clofazimine at 20 mg/kg and rifapentine resulted in increased activity in the mouse model. The combination of clofazimine and rifapentine (or rifabutin) appears to be an attractive regimen that should be evaluated for the treatment of human infections due to M. avium complex.
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Ethionamide
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Rifamycin drugs (i.e., rifampin, rifabutin, and rifapentine) are essential for short-course chemotherapy in persons with active tuberculosis (TB). However, adverse drug-drug interactions complicate the concurrent use of rifamycins and protease inhibitor drugs in persons with active TB who also are infected with human immunodeficiency virus (HIV-TB). CDC has recommended use of rifabutin in place of rifampin in multidrug regimens for the treatment of active TB in HIV-TB because rifabutin can be administered with antiretroviral treatment regimens that include protease inhibitors (1,2). These recommendations included twice-weekly intermittent therapy. Because intermittent rifabutin-based regimens had not been evaluated in clinical trials of HIV-TB, CDC's TB Trials Consortium (TBTC) initiated TBTC Study 23, a single-arm trial of twice-weekly rifabutin-based therapy for treatment of HIV-TB.
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There is renewed interest in the rifamycins, primarily from evidence that higher doses than have been previously used may allow a markedly shortened treatment of active and latent tuberculosis (TB). We review recent studies of the pharmacokinetics, pharmacodynamics and pharmacogenomics of rifampicin, rifapentine and rifabutin. The rifamycins have complex metabolic pathways and, therefore, have wide interpatient variability in drug exposure (10-fold or greater). Some of the reasons for the broad range in rifamycin exposure are now being elucidated: body weight, disease state, ingestion with food and polymorphisms in genes for drug transporter proteins. Children require 2- to 3- fold higher doses of rifampicin and rifapentine than adults do. Greater rifamycin exposure is closely correlated with bactericidal and sterilizing activities in the mouse model of TB treatment. The use of high-dose rifampicin and daily rifapentine allows treatment to be shortened to 3 months in the mouse model, and clinical trials are under way to evaluate these regimens in humans. Little is known about the relationship between rifamycin dose and toxicity, when daily dosing is used. New ways of using an old drug class – the rifamycins – may markedly improve TB treatment yet again.
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Rifabutin
Rifamycin
Pharmacogenomics
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