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Mycobacterium abscessus HelR interacts with RNA polymerase to confer intrinsic rifamycin resistance.Molecular Cell Sep 2022Rifampicin (RIF), the frontline drug against M. tuberculosis, is completely ineffective against M. abscessus, partially due to the presence of an...
Rifampicin (RIF), the frontline drug against M. tuberculosis, is completely ineffective against M. abscessus, partially due to the presence of an ADP-ribosyltransferase (Arr) that inactivates RIF. Using RNA-seq, we show that exposure of M. abscessus to sublethal doses of RIF and Rifabutin (RBT), a close analog of RIF, results in an ∼25-fold upregulation of Mab_helR in laboratory and clinical isolates. An isogenic deletion in Mab_helR results in RIF/RBT hypersensitivity, and overexpression of Mab_helR confers RIF tolerance in M. tuberculosis. We demonstrate an increased HelR-RNAP association in RIF-exposed bacteria and a MabHelR-mediated dissociation of RNAP from stalled initiation complexes in vitro. Finally, we show that the tip of the PCh-loop of Mab_helR, present in proximity to RIF, is critical for conferring RIF resistance but dispensable for dissociation of stalled RNAP complexes, suggesting that HelR-mediated RIF resistance requires a step in addition to displacement of RIF-stalled RNAP.
Topics: DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium abscessus; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins; Tuberculosis
PubMed: 35905736
DOI: 10.1016/j.molcel.2022.06.034 -
Helicobacter Aug 2022Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects...
BACKGROUND
Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects are concerning. This study assessed the efficacy and safety of 7-day rifabutin, amoxicillin, and vonoprazan triple therapy as third- or later-line treatment for H. pylori infection.
MATERIALS AND METHODS
Patients who did not respond to second-line therapy were enrolled. After H. pylori infection was confirmed with the culture method, the patients received rifabutin-containing triple therapy (20 mg vonoprazan b.i.d., 500 mg amoxicillin q.i.d., and 150 mg rifabutin q.d.) for 7 days. Twelve weeks after the eradication therapy, successful eradication was confirmed using a C urea breath test or the H. pylori stool antigen test. The results obtained from our previous study that reported a 10-day or 14-day esomeprazole based rifabutin-containing triple therapy as a third- or fourth-line rescue therapy treated patients were used as historical control. We determined the minimum inhibitory concentrations of amoxicillin and rifabutin. We also evaluated whether the patients were positive for the mutation of the rpoB gene.
RESULTS
Intention-to-treat and per-protocol analyses showed that our regimen resulted in a high eradication rate (91.2%, 95% CI: 84%-99% and 92.7%, 95% CI: 86%-100%, respectively). Adverse events occurred in 31.6% of the patients, and two patients discontinued the therapy.
CONCLUSIONS
This is the first study to evaluate the efficacy and safety of a 7-day low-dose rifabutin-based triple therapy with vonoprazan and amoxicillin. Our results suggest that our regimen was effective and safe as a third- or later-line H. pylori eradication regimen. To clarify what component in this regimen are critical, subsequent studies using a factorial design (comparing vonoprazan-amoxicillin dual therapy vs. vonoprazan-rifabutin triple therapy) will be needed.
Topics: Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Humans; Proton Pump Inhibitors; Rifabutin; Treatment Outcome
PubMed: 35644041
DOI: 10.1111/hel.12900 -
Antimicrobial Agents and Chemotherapy Aug 2018Repurposing drugs may be useful as an add-on in the treatment of pulmonary infections, which are particularly difficult to cure. naturally produces a β-lactamase,...
Repurposing drugs may be useful as an add-on in the treatment of pulmonary infections, which are particularly difficult to cure. naturally produces a β-lactamase, Bla, which is inhibited by avibactam. The recommended regimens include imipenem, which is hydrolyzed by Bla and used without any β-lactamase inhibitor. Here, we determine whether the addition of rifabutin improves the activity of imipenem alone or in combination with avibactam against CIP104536. Rifabutin at 16 μg/ml was only bacteriostatic (MIC of 4 μg/ml) and was moderately synergistic in combination with imipenem (fractional inhibitory concentration [FIC] index of 0.38). Addition of rifabutin (16 μg/ml) moderately increased killing by a low (8 μg/ml) but not by a high (32 μg/ml) concentration of imipenem. Addition of avibactam (4 μg/ml) did not further increase killing by the former combination. In infected macrophages, rifabutin (16 μg/ml) increased the activity of imipenem at 8 and 32 μg/ml, achieving 3- and 100-fold reductions in the numbers of intracellular bacteria, respectively. Avibactam (16 μg/ml) improved killing by imipenem at 8 μg/ml. A 5-fold killing was obtained for a triple combination comprising avibactam (16 μg/ml) and therapeutically achievable doses of imipenem (8 μg/ml) and rifabutin (1 μg/ml). These results indicate that the imipenem-rifabutin combination should be further considered for the treatment of pulmonary infections in cystic fibrosis patients and that addition of a β-lactamase inhibitor might improve its efficacy. Mechanistically, the impact of Bla inhibition by avibactam on antibiotic activity was assessed by comparing CIP104536 and a β-lactamase-deficient derivative.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Imipenem; Microbial Sensitivity Tests; Mycobacterium abscessus; Rifabutin
PubMed: 29866869
DOI: 10.1128/AAC.00623-18 -
Antimicrobial Agents and Chemotherapy Jan 2021Current treatment options for lung disease caused by complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform...
Current treatment options for lung disease caused by complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the bactericidal activity of single drugs against actively multiplying and net nonreplicating populations in nutrient-rich and nutrient-starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing , respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and nonreplicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved Overall, these data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for infections. This rich data set of differential time- and concentration-dependent activity of drugs, alone and together, against also highlights several issues affecting interpretation and translation of findings.
Topics: Anti-Bacterial Agents; Diarylquinolines; Humans; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Nutrients; Pharmaceutical Preparations; Rifabutin
PubMed: 33168614
DOI: 10.1128/AAC.02179-20 -
World Journal of Gastroenterology Feb 2014Helicobacter pylori is a highly successful bacterium with a high global prevalence and the infection carries significant disease burden. It is also becoming increasingly... (Review)
Review
Helicobacter pylori is a highly successful bacterium with a high global prevalence and the infection carries significant disease burden. It is also becoming increasingly difficult to eradicate and the main reason for this is growing primary antibiotic resistance rates in a world where antibiotics are frequently prescribed and readily available. Despite knowing much more about the bacterium since its discovery, such as its genomic makeup and pathogenesis, we have seen declining treatment success. Therefore, clinicians today must be prepared to face one, two or even multiple treatment failures, and should be equipped with sufficient knowledge to decide on the appropriate salvage therapy when this happens. This article discusses the factors contributing to treatment failure and reviews the second and third-line treatment strategies that have been investigated. Established empiric second line treatment options include both bismuth based quadruple therapy and levofloxacin based triple therapy. Antibiotic testing is recommended prior to initiating third line treatment. In the event that antibiotic susceptibility testing is unavailable, third line treatment options include rifabutin, rifaximin and sitafloxacin based therapies.
Topics: Anti-Bacterial Agents; Bismuth; Drug Resistance, Bacterial; Drug Therapy, Combination; Fluoroquinolones; Helicobacter Infections; Helicobacter pylori; Humans; Levofloxacin; Metronidazole; Moxifloxacin; Ofloxacin; Rifabutin; Rifamycins; Rifaximin; Salvage Therapy; Virulence Factors
PubMed: 24587627
DOI: 10.3748/wjg.v20.i6.1517 -
European Journal of Drug Metabolism and... Jul 2023People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to...
BACKGROUND
People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to reach maximal enzyme induction and to return to baseline enzyme levels has not been thoroughly characterized.
OBJECTIVE
The aim of this study was to evaluate the onset and disappearance of dolutegravir [uridine diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 substrate] and raltegravir (UGT1A1 substrate) induction with strong and moderate inducers using physiologically based pharmacokinetic (PBPK) modeling.
METHODS
The predictive performance of the PBPK model to simulate dolutegravir and raltegravir pharmacokinetics and to reproduce the strength of induction was verified using clinical drug-drug interaction studies (steady-state induction) and switch studies (residual induction). The model was considered verified when the predictions were within 2-fold of the observed data. One hundred virtual individuals (50% female) were generated to simulate the unstudied scenarios. The results were used to calculate the fold-change in CYP3A4 and UGT1A1 enzyme levels upon initiation and discontinuation of strong (rifampicin) or moderate (efavirenz or rifabutin) inducers.
RESULTS
The time for reaching maximal induction and subsequent disappearance of CYP3A4 induction was 14 days for rifampicin and efavirenz but 7 days for rifabutin. The distinct timelines for the moderate inducers relate to their different half-lives and plasma concentrations. The induction and de-induction processes were more rapid for UGT1A1.
CONCLUSIONS
Our simulations support the common practice of maintaining the adjusted dosage of a drug for another 2 weeks after stopping an inducer. Furthermore, our simulations suggest that an inducer should be administered for at least 14 days before conducting interaction studies to reach maximal induction.
Topics: Humans; Female; Male; Rifampin; Cytochrome P-450 CYP3A; Raltegravir Potassium; Drug Interactions; Glucuronosyltransferase; Rifabutin
PubMed: 37278880
DOI: 10.1007/s13318-023-00833-9 -
Journal of Biotechnology Jun 2006Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not... (Review)
Review
Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not necessarily been optimized for other desirable drug properties and thus can often be improved by structural modification. Using examples from the literature, this paper reviews the opportunities for increasing structural diversity among natural products by combinatorial biosynthesis, i.e., the genetic manipulation of biosynthetic pathways. It distinguishes between combinatorial biosynthesis in a narrower sense to generate libraries of modified structures, and metabolic engineering for the targeted formation of specific structural analogs. Some of the problems and limitations encountered with these approaches are also discussed. Work from the author's laboratory on ansamycin antibiotics is presented which illustrates some of the opportunities and limitations.
Topics: Anti-Bacterial Agents; Antineoplastic Agents, Phytogenic; Combinatorial Chemistry Techniques; Drug Design; Genetic Engineering; Maytansine; Molecular Structure; Polyketide Synthases; Rifabutin
PubMed: 16414140
DOI: 10.1016/j.jbiotec.2005.12.001 -
Journal of the International... 2022Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV)-infected people worldwide. Currently there are no studies examining the use of...
Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV)-infected people worldwide. Currently there are no studies examining the use of Rifabutin (RBN) and Dolutegravir (DTG) in co-infected persons. This is a case series of 4 co-infected patients receiving both agents who underwent Pharmacokinetic (PK) analysis. This is a retrospective chart review study of four patients diagnosed with both HIV and TB, receiving RBN and DTG and undergoing therapeutic drug monitoring. All 4 cases had lower than expected DTG concentrations at least once, including those on the current recommended dose of DTG with RBN, and even those receiving higher doses. Given the frequency of low DTG and RBN concentrations, therapeutic drug monitoring (TDM) for these drugs is advisable. Prospective clinical studies are needed to further determine the PK interactions between RBN and DTG, and virologic response to treatment.
Topics: Antibiotics, Antitubercular; HIV Infections; Heterocyclic Compounds, 3-Ring; Humans; Oxazines; Piperazines; Prospective Studies; Pyridones; Retrospective Studies; Rifabutin; Tuberculosis
PubMed: 36026587
DOI: 10.1177/23259582221111077 -
Synergistic Effects of Omadacycline with Other Antimicrobial Agents against Mycobacterium abscessus.Antimicrobial Agents and Chemotherapy Jun 2023The clinical importance of Mycobacterium abscessus species (MABS) infections has been increasing. However, the standard treatment regimens recommended in the current...
The clinical importance of Mycobacterium abscessus species (MABS) infections has been increasing. However, the standard treatment regimens recommended in the current guidelines often result in unfavorable outcomes. Therefore, we investigated the activity of omadacycline (OMC), a novel tetracycline, against MABS to explore its potential as a novel therapeutic option. The drug susceptibilities of 40 Mycobacterium abscessus subsp. (Mab) clinical strains obtained from the sputum of 40 patients from January 2005 to May 2014 were investigated. The MIC results for OMC, amikacin (AMK), clarithromycin (CLR), clofazimine (CLO), imipenem (IPM), rifabutin (RFB), and tedizolid (TZD) alone and their combined effects (with OMC) were examined using the checkerboard method. Additionally, we studied the differences in the effectiveness of the antibiotic combinations based on the colony morphotype of Mab. The MIC and MIC of OMC alone were 2 and 4 μg/mL, respectively. The combinations of OMC with AMK, CLR, CLO, IPM, RFB, and TZD showed synergy against 17.5%, 75.8%, 25.0%, 21.1%, 76.9%, and 34.4% of the strains, respectively. Additionally, OMC combined with CLO (47.1% versus 9.5%, 0.023) or TZD (60.0% versus 12.5%, 0.009) showed significantly higher synergy against strains with rough morphotypes than those with smooth morphotypes. In conclusion, the checkerboard analyses revealed that the synergistic effects of OMC were observed most frequently with RFB, followed by CLR, TZD, CLO, IPM, and AMK. Furthermore, OMC tended to be more effective against rough-morphotype Mab strains.
Topics: Humans; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Clarithromycin; Amikacin; Anti-Infective Agents; Mycobacterium; Rifabutin; Tetracyclines; Microbial Sensitivity Tests
PubMed: 37154742
DOI: 10.1128/aac.01579-22 -
Archives of Toxicology Aug 2023Compared to rifampicin (600 mg/day), standard doses of rifabutin (300 mg/day) have a lower risk of drug-drug interactions due to induction of cytochrome P450 3A4...
Compared to rifampicin (600 mg/day), standard doses of rifabutin (300 mg/day) have a lower risk of drug-drug interactions due to induction of cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (Pgp/ABCB1) mediated by the pregnane X receptor (PXR). However, clinical comparisons with equal rifamycin doses or in vitro experiments respecting actual intracellular concentrations are lacking. Thus, the genuine pharmacological differences and the potential molecular mechanisms of the discordant perpetrator effects are unknown. Consequently, the cellular uptake kinetics (mass spectrometry), PXR activation (luciferase reporter gene assays), and impact on CYP3A4 and Pgp/ABCB1 expression and activity (polymerase chain reaction, enzymatic assays, flow cytometry) were evaluated in LS180 cells after treatment with different rifampicin or rifabutin concentrations for variable exposure times and eventually normalized to actual intracellular concentrations. In addition, inhibitory effects on CYP3A4 and Pgp activities were investigated. While rifampicin is poorly taken up by LS180 cells, it strongly activates PXR and leads to enhanced expression and activity of CYP3A4 and Pgp. In contrast, rifabutin is a significantly less potent and less efficient PXR activator and gene inducer, despite sixfold to eightfold higher intracellular accumulation. Finally, rifabutin is a potent inhibitor of Pgp (IC = 0.3 µM) compared to rifampicin (IC = 12.9 µM). Together, rifampicin and rifabutin significantly differ by their effects on the regulation and function of CYP3A4 and Pgp, even when controlled for intracellular concentrations. Rifabutin's concurrent Pgp inhibitory action might partly compensate the inducing effects, explaining its weaker clinical perpetrator characteristics.
Topics: Rifampin; Cytochrome P-450 CYP3A; Rifabutin; Receptors, Steroid; Drug Interactions
PubMed: 37285043
DOI: 10.1007/s00204-023-03531-2