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Cold Spring Harbor Perspectives in... Jul 2016Rifamycins inhibit RNA polymerase of most bacterial genera. Rifampicin remains part of combination therapy for treating tuberculosis (TB), and for treating Gram-positive... (Review)
Review
Rifamycins inhibit RNA polymerase of most bacterial genera. Rifampicin remains part of combination therapy for treating tuberculosis (TB), and for treating Gram-positive prosthetic joint and valve infections, in which biofilms are prominent. Rifabutin has use for AIDS patients in treating mycobacterial infections TB and Mycobacterium avium complex (MAC), having fewer drug-drug interactions that interfere with AIDS medications. Rifabutin is occasionally used in combination to eradicate Helicobacter pylori (peptic ulcer disease). Rifapentine has yet to fulfill its potential in reducing time of treatment for TB. Rifaximin is a monotherapeutic agent to treat gastrointestinal (GI) disorders, such as hepatic encephalopathy, irritable bowel syndrome, and travelers' diarrhea. Rifaximin is confined to the GI tract because it is not systemically absorbed on oral dosing, achieving high local concentrations, and showing anti-inflammatory properties in addition to its antibacterial activity. Resistance issues are unavoidable with all the rifamycins when the bioburden is high, because of mutations that modify RNA polymerase.
Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Drug Therapy, Combination; Gastrointestinal Diseases; Humans; Rifabutin; Rifampin; Rifamycins; Rifaximin; Tuberculosis
PubMed: 27270559
DOI: 10.1101/cshperspect.a027011 -
BMJ Open Ophthalmology 2022This review assesses different clinical aspects of the various known drug-induced corneal deposits, based on the corneal layer involved (epithelium, stroma and/or... (Review)
Review
This review assesses different clinical aspects of the various known drug-induced corneal deposits, based on the corneal layer involved (epithelium, stroma and/or endothelium), and based on the drug class. The most well-known condition caused by drug deposits is vortex keratopathy, or corneal verticillata, which is a whorl-like opacity in the corneal epithelium. Vortex keratopathy is commonly caused by certain cationic amphiphilic drugs such as amiodarone, antimalarials, suramin, tamoxifen, chlorpromazine and non-steroidal anti-inflammatory drugs. These deposits usually occur once a certain dose of the drug is reached. Most cases present with mild to moderate symptoms with minimal visual impairment. Most of these deposits resolve automatically, after months to years of drug cessation. Notably, other drug classes can cause deposits in all three layers of the cornea. Chlorpromazine, gold, rifabutin, indomethacin and tyrosine kinase inhibitors can cause stromal deposits, with reduced visual acuity when the anterior stroma is involved. Chlorpromazine and rifabutin can also cause deposits in the endothelial layer of the cornea. Regardless of the type of corneal deposit, local therapies such as topical lubricants or corticosteroids may help improve symptoms. Drug cessation or modification can also be helpful but should be weighed against the systemic risks of the underlying disease.
Topics: Chlorpromazine; Corneal Dystrophies, Hereditary; Corneal Opacity; Humans; Rifabutin; Vision Disorders
PubMed: 35415268
DOI: 10.1136/bmjophth-2021-000943 -
Expert Opinion on Drug Discovery Sep 2019: The treatment of lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key... (Review)
Review
: The treatment of lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. : In this review, the authors discuss the rifamycins as a reemerging drug class for treating infections. The authors focus on the differential potency of rifampicin and rifabutin against in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. : While repurposing rifabutin for lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen.
Topics: Animals; Anti-Bacterial Agents; Drug Repositioning; Humans; Lung Diseases; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Rifabutin; Rifampin; Rifamycins
PubMed: 31195849
DOI: 10.1080/17460441.2019.1629414 -
Frontiers in Cellular and Infection... 2023We aimed to evaluate the activity of PBTZ169 and pretomanid against non-tuberculous mycobacteriosis (NTM) and .
OBJECTIVES
We aimed to evaluate the activity of PBTZ169 and pretomanid against non-tuberculous mycobacteriosis (NTM) and .
METHODS
The minimum inhibitory concentrations (MICs) of 11 antibiotics, against slow-growing mycobacteria (SGMs) and rapid-growing mycobacteria (RGMs) were tested using the microplate alamarBlue assay. The activities of bedaquiline, clofazimine, moxifloxacin, rifabutin, PBTZ169 and pretomanid against four common NTMs were assessed in murine models.
RESULTS
PBTZ169 and pretomanid had MICs of >32 μg/mL against most NTM reference and clinical strains. However, PBTZ169 was bactericidal against (3.33 and 1.49 log10 CFU reductions in the lungs and spleen, respectively) and (2.29 and 2.24 CFU reductions in the lungs and spleen, respectively) in mice, and bacteriostatic against Mycobacterium avium and . Pretomanid dramatically decreased the CFU counts of (3.12 and 2.30 log10 CFU reductions in the lungs and spleen, respectively), whereas it showed moderate inhibition of and . Bedaquiline, clofazimine, and moxifloxacin showed good activities against four NTMs and . Rifabutin did not inhibit and in mice.
CONCLUSION
PBTZ169 appears to be a candidate for treating four common NTM infections. Pretomanid was more active against , and than against .
Topics: Animals; Mice; Mycobacterium abscessus; Mycobacterium avium; Mycobacterium fortuitum; Mycobacterium chelonae; Clofazimine; Moxifloxacin; Mice, Inbred BALB C; Anti-Bacterial Agents; Nontuberculous Mycobacteria; Mycobacterium Infections; Rifabutin; Mycobacterium Infections, Nontuberculous; Microbial Sensitivity Tests
PubMed: 37077530
DOI: 10.3389/fcimb.2023.1115530 -
Molecular Pharmacology May 2011The benzoquinone ansamycins inhibit the ATPase activity of the 90-kDa heat shock protein (Hsp90), disrupting the function of numerous client proteins involved in...
The benzoquinone ansamycins inhibit the ATPase activity of the 90-kDa heat shock protein (Hsp90), disrupting the function of numerous client proteins involved in oncogenesis. In this study, we examine the role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the metabolism of trans- and cis-amide isomers of the benzoquinone ansamycins and their mechanism of Hsp90 inhibition. Inhibition of purified human Hsp90 by a series of benzoquinone ansamycins was examined in the presence and absence of NQO1, and their relative rate of NQO1-mediated reduction was determined. Computational-based molecular docking simulations indicated that the trans- but not the cis-amide isomers of the benzoquinone ansamycins could be accommodated by the NQO1 active site, and the ranking order of binding energies correlated with the relative reduction rate using purified human NQO1. The trans-cis isomerization of the benzoquinone ansamycins in Hsp90 inhibition has been disputed in recent reports. Previous computational studies have used the closed or cocrystallized Hsp90 structures in an attempt to explore this isomerization step; however, we have successfully docked both the trans- and cis-amide isomers of the benzoquinone ansamycins into the open Hsp90 structure. The results of these studies indicate that both trans- and cis-amide isomers of the hydroquinone ansamycins exhibited increased binding affinity for Hsp90 relative to their parent quinones. Our data support a mechanism in which trans- rather than cis-amide forms of benzoquinone ansamycins are metabolized by NQO1 to hydroquinone ansamycins and that Hsp90-mediated trans-cis isomerization via tautomerization plays an important role in subsequent Hsp90 inhibition.
Topics: Benzoquinones; Catalytic Domain; Chromatography, High Pressure Liquid; HSP90 Heat-Shock Proteins; Hydroquinones; Lactams, Macrocyclic; Mass Spectrometry; Models, Molecular; NAD(P)H Dehydrogenase (Quinone); Protein Conformation
PubMed: 21285336
DOI: 10.1124/mol.110.070086 -
Applied and Environmental Microbiology Aug 2005Geldanamycin and the closely related herbimycins A, B, and C were the first benzoquinone ansamycins to be extensively studied for their antitumor properties as...
Geldanamycin and the closely related herbimycins A, B, and C were the first benzoquinone ansamycins to be extensively studied for their antitumor properties as small-molecule inhibitors of the Hsp90 protein chaperone complex. These compounds are produced by two different Streptomyces hygroscopicus strains and have the same modular polyketide synthase (PKS)-derived carbon skeleton but different substitution patterns at C-11, C-15, and C-17. To set the stage for structural modification by genetic engineering, we previously identified the gene cluster responsible for geldanamycin biosynthesis. We have now cloned and sequenced a 115-kb segment of the herbimycin biosynthetic gene cluster from S. hygroscopicus AM 3672, including the genes for the PKS and most of the post-PKS tailoring enzymes. The similarities and differences between the gene clusters and biosynthetic pathways for these closely related ansamycins are interpreted with support from the results of gene inactivation experiments. In addition, the organization and functions of genes involved in the biosynthesis of the 3-amino-5-hydroxybenzoic acid (AHBA) starter unit and the post-PKS modifications of progeldanamycin were assessed by inactivating the subclusters of AHBA biosynthetic genes and two oxygenase genes (gdmM and gdmL) that were proposed to be involved in formation of the geldanamycin benzoquinoid system. A resulting novel geldanamycin analog, KOS-1806, was isolated and characterized.
Topics: Aminobenzoates; Antibiotics, Antineoplastic; Bacterial Proteins; Benzoquinones; Cloning, Molecular; Gene Deletion; Hydroxybenzoates; Lactams, Macrocyclic; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Multigene Family; Polyketide Synthases; Quinones; Rifabutin; Sequence Analysis, DNA; Streptomyces
PubMed: 16085885
DOI: 10.1128/AEM.71.8.4862-4871.2005 -
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 -
International Journal of Infectious... Dec 2017
Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Mycobacterium tuberculosis; Rifabutin; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 29122690
DOI: 10.1016/j.ijid.2017.10.019 -
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 -
The American Journal of Gastroenterology Aug 2023
Topics: Humans; Rifabutin; Cost-Benefit Analysis; Anti-Bacterial Agents; Pyrroles; Drug Therapy, Combination; Proton Pump Inhibitors; Helicobacter pylori
PubMed: 37094105
DOI: 10.14309/ajg.0000000000002248