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Environmental Health Perspectives Nov 1994Animal studies have demonstrated that the mouse and rabbit are far more responsive to the inductive properties of rifamycin derivatives than the rat and guinea pig. The... (Review)
Review
Animal studies have demonstrated that the mouse and rabbit are far more responsive to the inductive properties of rifamycin derivatives than the rat and guinea pig. The rat hepatic cytochrome P450 system seems to be resistant to the action of rifampicin unless very high doses are used. Mouse hepatic microsomal mixed-function oxidase activity is markedly increased by repeated dosing with rifampicin, whereas administration of rifabutin may be ineffective. In humans, both rifampicin and rifabutin are extensively metabolized and induce their own metabolism. The induced metabolic pathways remain essentially unknown. Under autoinduction conditions, the elimination half-life of rifampicin decreases, whereas that of rifabutin is not altered. Although the effects of repeated administration of rifampicin and rifabutin on the various forms of cytochrome P450 in humans have not been extensively examined, there is convincing evidence that the P4503A subfamily is induced by either drug, whereas the P4501A subfamily and P4502D6 do not appear to be affected by rifampicin. Limited reliable information is available concerning the induction of human glucuronyltransferase activities by rifampicin and rifabutin which, however, do not seem to influence zidovudine glucuronide formation in healthy subjects.
Topics: Animals; Cytochrome P-450 Enzyme System; Enzyme Induction; Female; Humans; Male; Mice; Microsomes, Liver; Rabbits; Rats; Rifabutin; Rifampin; Species Specificity
PubMed: 7698069
DOI: 10.1289/ehp.94102s9101 -
PloS One 2016The emergence of bacteria that are resistant to many currently used drugs emphasizes the need to discover and develop new antibiotics that are effective against such...
PURPOSE
The emergence of bacteria that are resistant to many currently used drugs emphasizes the need to discover and develop new antibiotics that are effective against such multi-resistant strains. Kendomycin is a novel polyketide that has a unique quinone methide ansa structure and various biological properties. This compound exhibits strong antibacterial activity against Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Despite the promise of kendomycinin in several therapeutic areas, its mode of action has yet to be identified.
METHODS
In this study, we used a multidisciplinary approach to gain insight into the antibacterial mechanism of this compound.
RESULTS
The antibacterial activity of kendomycin appears to be bacteriostatic rather than bactericidal. Kendomycin inhibited the growth of the MRSA strain COL at a low concentration (MIC of 5 μg/mL). Proteomic analysis and gene transcription profiling of kendomycin-treated cells indicated that this compound affected the regulation of numerous proteins and genes involved in central metabolic pathways, such as the tricarboxylic acid (TCA) cycle (SdhA) and gluconeogenesis (PckA and GapB), cell wall biosynthesis and cell division (FtsA, FtsZ, and MurAA), capsule production (Cap5A and Cap5C), bacterial programmed cell death (LrgA and CidA), the cellular stress response (ClpB, ClpC, ClpP, GroEL, DnaK, and GrpE), and oxidative stress (AhpC and KatA). Electron microscopy revealed that kendomycin strongly affected septum formation during cell division. Most kendomycin-treated cells displayed incomplete septa with abnormal morphology.
CONCLUSIONS
Kendomycin might directly or indirectly affect the cell division machinery, protein stability, and programmed cell death in S. aureus. Additional studies are still needed to obtain deeper insight into the mode of action of kendomycin.
Topics: Acetates; Anti-Bacterial Agents; Electrophoresis, Gel, Two-Dimensional; Gene Expression Profiling; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Proteome; Rifabutin
PubMed: 26795276
DOI: 10.1371/journal.pone.0146165 -
Microbiology Spectrum Aug 2022Mycobacterium abscessus is an emerging human pathogen leading to significant morbidity and even mortality, intrinsically resistant to almost all the antibiotics...
Mycobacterium abscessus is an emerging human pathogen leading to significant morbidity and even mortality, intrinsically resistant to almost all the antibiotics available and so can be a nightmare. Mechanisms of its intrinsic resistance remain not fully understood. Here, we selected and confirmed an M. abscessus transposon mutant that is hypersensitive to multiple drugs including rifampin, rifabutin, vancomycin, clofazimine, linezolid, imipenem, levofloxacin, cefoxitin, and clarithromycin. The gene encoding a putative arabinosyltransferase C was found to be disrupted, using a newly developed highly-efficient strategy combining next-generation sequencing and multiple PCR. Furthermore, selectable marker-free deletion of recapitulated the hypersensitive phenotype. Disruption of resulted in an inability to synthesize lipoarabinomannan and markedly enhanced its cell envelope permeability. Complementing or M. tuberculosis restored the resistance phenotype. Importantly, treatment of M. abscessus with ethambutol, a first-line antituberculosis drug targeting arabinosyltransferases of M. tuberculosis, largely sensitized M. abscessus to multiple antibiotics . We finally tested activities of six selected drugs using a murine model of sustained M. abscessus infection and found that linezolid, rifabutin, and imipenem were active against the deletion strain. These results identified MAB_0189 as a crucial determinant of intrinsic resistance of M. abscessus, and optimizing inhibitors targeting MAB_0189 might be a strategy to disarm the intrinsic multiple antibiotic resistance of M. abscessus. Mycobacterium abscessus is intrinsically resistant to most antibiotics, and treatment of its infections is highly challenging. The mechanisms of its intrinsic resistance remain not fully understood. Here we found a transposon mutant hypersensitive to a variety of drugs and identified the transposon inserted into the (orthologous coding arabinosyltransferase, EmbC) gene by using a newly developed rapid and efficient approach. We further verified that the gene played a significant role in its intrinsic resistance by decreasing the cell envelope permeability through affecting the production of lipoarabinomannan in its cell envelope. Lastly, we found the arabinosyltransferases inhibitor, ethambutol, increased activities of nine selected drugs . Knockout of made M. abscessus become susceptible to 3 drugs in mice. These findings indicated that potential powerful M. abscessus EmbC inhibitor might be used to reverse the intrinsic resistance of M. abscessus to multiple drugs.
Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Ethambutol; Humans; Imipenem; Linezolid; Mice; Mice, Knockout; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Pentosyltransferases; Permeability; Rifabutin; Tuberculosis
PubMed: 35946941
DOI: 10.1128/spectrum.02763-21 -
Biochemical Pharmacology Apr 2012Quinones represent a large and diverse class of antitumor drugs and many quinones are approved for clinical use or are currently undergoing evaluation in clinical... (Review)
Review
Quinones represent a large and diverse class of antitumor drugs and many quinones are approved for clinical use or are currently undergoing evaluation in clinical trials. For many quinones reduction to the hydroquinone has been shown to play a key role in their antitumor activity. The two-electron reduction of quinones by NQO1 has been shown to be an efficient pathway to hydroquinone formation. NQO1 is expressed at high levels in many human solid tumors making this enzyme ideally suited for intracellular drug activation. Cellular levels of NQO1 are influenced by the NQO1*2 polymorphism. Individuals homozygous for the NQO1*2 allele are NQO1 null and homozygous NQO1*2*2 cell lines have been shown to be more resistant to antitumor quinones when compared to isogenic cell lines overexpressing NQO1. In this review we will discuss the role of NQO1 in the sensitivity and resistance of human cancers to the quinone antitumor drugs mitomycin C, β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors including 17-AAG. The role of NQO1 in the bioreductive activation of mitomycin C remains controversial but pre-clinical data strongly suggests a role for NQO1 in the activation of β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors. Despite a large volume of preclinical data demonstrating that NQO1 is an important determinant of sensitivity to these antitumor quinones there is little information on whether the clinical response to these agents is influenced by the NQO1*2 polymorphism. The availability of simple assays for the determination of the NQO1*2 polymorphism should facilitate clinical testing of this hypothesis.
Topics: Antineoplastic Agents; Benzoquinones; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mitomycin; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Polymorphism, Genetic; Quinones; Rifabutin
PubMed: 22209713
DOI: 10.1016/j.bcp.2011.12.017 -
Nature Communications Aug 2022Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires...
Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires strict adherence to drug regimens for prolonged periods of time. Long-acting (LA) delivery systems have the potential to improve adherence. Here, we show the development of LA injectable drug formulations of the anti-TB drug rifabutin made of biodegradable polymers and biocompatible solvents that solidifies after subcutaneous injection. Addition of amphiphilic compounds increases drug solubility, allowing to significantly increase formulation drug load. Solidified implants have organized microstructures that change with formulation composition. Higher drug load results in smaller pore size that alters implant erosion and allows sustained drug release. The translational relevance of these observations in BALB/c mice is demonstrated by (1) delivering high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb infection, and (3) clearing acute Mtb infection from the lung and other tissues.
Topics: Animals; Antitubercular Agents; Drug Delivery Systems; Mice; Mycobacterium tuberculosis; Rifabutin; Tuberculosis
PubMed: 35941109
DOI: 10.1038/s41467-022-32043-3 -
British Journal of Clinical Pharmacology Mar 2023Rifampicin, a potent enzyme inducer, causes marked reduction of dolutegravir exposure. Rifabutin, a less potent enzyme inducer, may offer an alternative to rifampicin....
Rifampicin, a potent enzyme inducer, causes marked reduction of dolutegravir exposure. Rifabutin, a less potent enzyme inducer, may offer an alternative to rifampicin. We aimed to characterize the population pharmacokinetics of dolutegravir when co-administered with rifabutin. We extended an existing dolutegravir model to include data from volunteers co-administered with dolutegravir 50 mg and rifabutin 300 mg once daily. We ran simulations of dolutegravir with and without rifabutin co-administration and compare dolutegravir trough concentrations with the IC and EC of 0.064 and 0.3 mg/L, respectively. Rifabutin decreased dolutegravir's volume of distribution by 33.1% (95% confidence interval 25.1%-42.3%) but did not affect the area under the concentration-time curve. Simulations showed that when 50 mg dolutegravir is co-administered with rifabutin once daily, the probability to attain trough concentrations above the IC of 0.064 mg/L is more than 99%. Therefore, there is no need for dolutegravir dose adjustment. Rifabutin may offer an alternative to rifampicin for the treatment of HIV/tuberculosis co-infected individuals.
Topics: Humans; Rifabutin; Rifampin; HIV Infections; Drug Interactions
PubMed: 36385424
DOI: 10.1111/bcp.15604 -
Journal of the International... 2013Drug-induced lupus (DIL) is a rare adverse reaction to medications with features resembling idiopathic systemic lupus erythromatosis. Rifabutin/rifamycins have only... (Review)
Review
Drug-induced lupus (DIL) is a rare adverse reaction to medications with features resembling idiopathic systemic lupus erythromatosis. Rifabutin/rifamycins have only rarely been reported as a cause of DIL, and no cases have been reported in blacks. A 55-year-old African American woman with HIV presented with severe generalized arthralgias and recurrent oral ulcers while receiving treatment for tuberculous meningitis. Arthralgias, which began in her knees after 5 weeks of antituberculous therapy, progressed to involve the joints in the ankles, wrists, and hands. She had no associated fever or rash. When she had these symptoms her antinuclear antibody (ANA) was 1:1280 homogenous pattern, antidouble stranded DNA was negative, antihistone antibody was strongly positive, anti-smith and antiribonucleoprotein (anti-RNP) were negative. Her symptoms resolved within 2 months of stopping rifabutin while continuing other antituberculous medications and her ANA titer started to decrease. We review the existing literature on this subject.
Topics: Antibiotics, Antitubercular; Female; HIV Infections; Humans; Lupus Erythematosus, Systemic; Middle Aged; Rifabutin; Tuberculosis
PubMed: 23442494
DOI: 10.1177/2325957412473647 -
Molecules (Basel, Switzerland) Nov 2021In the course of screening new streptomycete strains, the strain sp. Cl 58-27 caught our attention due to its interesting secondary metabolite production profile. Here,...
In the course of screening new streptomycete strains, the strain sp. Cl 58-27 caught our attention due to its interesting secondary metabolite production profile. Here, we report the isolation and characterization of an ansamycin natural product that belongs structurally to the already known kendomycins. The structure of the new kendomycin E was elucidated using NMR spectroscopy, and the corresponding biosynthetic gene cluster was identified by sequencing the genome of sp. Cl 58-27 and conducting a detailed analysis of secondary metabolism gene clusters using bioinformatic tools.
Topics: Biological Products; Multigene Family; Rifabutin; Secondary Metabolism; Streptomyces
PubMed: 34833926
DOI: 10.3390/molecules26226834 -
The Journal of Antibiotics Jul 1999The antifungal and antibacterial properties of the crude extract from Streptomyces sp. (strain Gö 40/10) encouraged us to perform a detailed analysis of its secondary...
The antifungal and antibacterial properties of the crude extract from Streptomyces sp. (strain Gö 40/10) encouraged us to perform a detailed analysis of its secondary metabolite pattern by chemical screening, which revealed the presence of at least 30 different compounds. Ten of the isolated 18 metabolites proved to be new. Remarkable are hydrogenated (3, 4) and glucosylated (5, 6, 7) 14-membered macrolides derived from cineromycin B, two gamma-butyrolactones (8, 9), the so far unknown naphthomycin K (14) and the collinolactones A and B. The constitution and relative stereochemistry of these metabolites were deduced from spectroscopic data. Finally the concept of our one strain/many compounds (OSMAC) method for exploring new microbial secondary metabolites is discussed.
Topics: 4-Butyrolactone; Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Fermentation; Lactones; Rifabutin; Streptomyces
PubMed: 10513843
DOI: 10.7164/antibiotics.52.635 -
Gastroenterologie Clinique Et Biologique Mar 2003Helicobacter pylori eradication failure generally concerns between 10 and 30% of the patients. When eradication failure occurs, it is necessary a) to try to identify the... (Review)
Review
Helicobacter pylori eradication failure generally concerns between 10 and 30% of the patients. When eradication failure occurs, it is necessary a) to try to identify the potential causes, b) to confirm the indication of eradicating H. pylori, and c) to choose a second line therapeutic strategy. Among the factors most frequently associated with failed eradication, are poor compliance, younger age, smoking, and weak gastric inflammatory activity. The major factor of resistance is related to the sensitivity of the bacterial strain to antibiotics used. In France, resistance to clarithromycin is around 10-15% and resistance to metronidazole around 30%. In order to limit development of resistance, it seems preferable to avoid associating clarithromycin and metronidazole in the first line treatment. At best, the first line treatment must follow the official recommendations (PPI-amoxicillin and clarithromycin). In the event of eradication failure, second line treatment calls upon tritherapy which, due to the low rate of resistance to amoxicillin, associates double-dose PPI, amoxicillin and the antibiotic not used during the first line treatment (metronidazole if clarithromycin was initially used and conversely). This approach allows to eradicate between 50 and 80% of the first-line failure patients. In case of further failure a culture with measurement of the strain sensitivity is required. Subsequent treatment associates PPI with the antibiotics to which the strain is sensitive for a longer duration. In some cases, other effective antibiotics, such as rifabutin, might be used in these circumstances.
Topics: Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Drug Resistance, Microbial; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Humans; Metronidazole; Penicillins; Recurrence; Rifabutin
PubMed: 12700506
DOI: No ID Found