scholarly journals In Vitro Activities of Different Inhibitors of Bacterial Transcription against Staphylococcus epidermidis Biofilm

2007 ◽  
Vol 51 (9) ◽  
pp. 3117-3121 ◽  
Author(s):  
Philippe Villain-Guillot ◽  
Maxime Gualtieri ◽  
Lionel Bastide ◽  
Jean-Paul Leonetti
Keyword(s):  
Rna Polymerase ◽  
Structural Properties ◽  
Medical Devices ◽  
Nosocomial Infections ◽  
Staphylococcus Epidermidis ◽  
Antibacterial Agents ◽  
Transcription Inhibitors ◽  
Bacterial Transcription ◽  
Transcription Inhibitor

ABSTRACT Staphylococcus epidermidis is a major cause of nosocomial infections because of its ability to form biofilms on the surface of medical devices. Only a few antibacterial agents are relatively active against biofilms, and rifampin, a transcription inhibitor, ranks among the most effective molecules against biofilm-related infections. Whether this efficacy is due to advantageous structural properties of rifampin or to the fact that the RNA polymerase is a favorable target remains unclear. In an attempt to answer this question, we investigated the action of different transcription inhibitors against S. epidermidis biofilm, including the newest synthetic transcription inhibitors. This comparison suggests that most of the antibiotics that target the RNA polymerase are active on S. epidermidis biofilms at concentrations close to their MICs. One of these compounds, CBR703, despite its high MIC ranks among the best antibiotics to eradicate biofilm-embedded bacteria.

Correlation between the activity of a 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole-insensitive puff and the synthesis of major heat-shock polypeptide, hsp70, in Chironomus thummi

1988 ◽  
Vol 66 (11) ◽  
pp. 1177-1185 ◽  
Author(s):  
D. Barettino ◽  
G. Morcillo ◽  
J. L. Díez ◽  
M. T. Carretero ◽  
M. J. Carmona
Keyword(s):  
Heat Shock ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Specific Inhibitor ◽  
In Vitro Transcription ◽  
The Other ◽  
Low Salt ◽  
Transcription Inhibitor ◽  
Chironomus Thummi

The induction of puff III-A3b, a major heat-shock puff in Chironomus thummi salivary cells, was insensitive to the transcription inhibitor 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB), whereas no transcriptional activity could be detected at the other heat-shock puffs in the presence of this drug. In these conditions, a polypeptide with the same Mr and isoform pattern as those of the major heat-shock polypeptide, hsp70, was synthesized. These results suggest that hsp70 is encoded by locus III-A3b. In addition to DRB insensitivity, incorporation of [3H]UTP on puff III-A3b took place in an in vitro transcription assay under low-salt conditions (100 mM NaCl); no labelling could be detected at the other heat-shock puffs under these conditions. Although DRB has been reported as a specific inhibitor of RNA polymerase II-directed transcription, and although the low-salt conditions were not propitious for the activity of this enzyme, RNA polymerase II was detected on puff III-A3b and on the other heat-shock puffs by immunofluorescence with anti-RNA polymerase II antibodies.

scholarly journals Therapeutic Targeting of the General RNA Polymerase II Transcription Machinery

2020 ◽  
Vol 21 (9) ◽  
pp. 3354 ◽  
Author(s):  
Ryan D. Martin ◽  
Terence E. Hébert ◽  
Jason C. Tanny
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Complex Diseases ◽  
Cellular Models ◽  
Transcription Machinery ◽  
Transcription Inhibitors ◽  
Preclinical And Clinical Studies ◽  
Rna Polymerase Ii Transcription ◽  
Rnapii Transcription

Inhibitors targeting the general RNA polymerase II (RNAPII) transcription machinery are candidate therapeutics in cancer and other complex diseases. Here, we review the molecular targets and mechanisms of action of these compounds, framing them within the steps of RNAPII transcription. We discuss the effects of transcription inhibitors in vitro and in cellular models (with an emphasis on cancer), as well as their efficacy in preclinical and clinical studies. We also discuss the rationale for inhibiting broadly acting transcriptional regulators or RNAPII itself in complex diseases.

scholarly journals Characterization of a Rifampin-Inactivating Glycosyltransferase from a Screen of Environmental Actinomycetes

2012 ◽  
Vol 56 (10) ◽  
pp. 5061-5069 ◽  
Author(s):  
Peter Spanogiannopoulos ◽  
Maulik Thaker ◽  
Kalinka Koteva ◽  
Nicholas Waglechner ◽  
Gerard D. Wright
Keyword(s):  
Antibiotic Resistance ◽  
Rna Polymerase ◽  
Draft Genome ◽  
Rrna Gene ◽  
Content Type ◽  
Reading Frame ◽  
Bacterial Transcription ◽  
Steady State Kinetics ◽  
Rifampin Resistance

ABSTRACTIdentifying and understanding the collection of all antibiotic resistance determinants presented in the global microbiota, the antibiotic resistome, provides insight into the evolution of antibiotic resistance and critical information for the development of future antimicrobials. The rifamycins are broad-spectrum antibiotics that target bacterial transcription by inhibition of RNA polymerase. Although mutational alteration of the drug target is the predominant mechanism of resistance to this family of antibiotics in the clinic, a number of diverse inactivation mechanisms have also been reported. In this report, we investigate a subset of environmental rifampin-resistant actinomycete isolates and identify a diverse collection of rifampin inactivation mechanisms. We describe a single isolate, WAC1438, capable of inactivating rifampin by glycosylation. A draft genome sequence of WAC1438 (most closely related toStreptomyces speibonae, according to a 16S rRNA gene comparison) was assembled, and the associated rifampin glycosyltransferase open reading frame,rgt1438, was identified. The role ofrgt1438in rifampin resistance was confirmed by its disruption in the bacterial chromosome, resulting in a loss of antibiotic inactivation and a 4-fold decrease in MIC. Interestingly, examination of the RNA polymerase β-subunit sequence of WAC1438 suggests that it harbors a resistant target and thus possesses dual mechanisms of rifamycin resistance. Using anin vitroassay with purified enzyme, Rgt1438 could inactivate a variety of rifamycin antibiotics with comparable steady-state kinetics constants. Our results identifyrgt1438as a rifampin resistance determinant from WAC1438 capable of inactivating an assortment of rifamycins, adding a new element to the rifampin resistome.

scholarly journals Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus

2020 ◽  
Vol 21 (16) ◽  
pp. 5772
Author(s):  
Adrian Jun Chu ◽  
Yangyi Qiu ◽  
Rachel Harper ◽  
Lin Lin ◽  
Cong Ma ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Antimicrobial Agents ◽  
Bacterial Pathogen ◽  
Cellular Respiration ◽  
Regulatory Pathways ◽  
Protein Levels ◽  
Transcription Inhibitors ◽  
Bacterial Transcription

The emergence of multidrug resistance in the clinically significant pathogen Staphylococcus aureus is a global health burden, compounded by a diminishing drug development pipeline, and a lack of approved novel antimicrobials. Our previously reported first-in-class bacterial transcription inhibitors “nusbiarylins” presented a promising prospect towards the discovery of novel antimicrobial agents with a novel mechanism. Here we investigated and characterised the lead nusbiarylin compound, MC4, and several of its chemical derivatives in both methicillin-resistant S. aureus (MRSA) and the S. aureus type strains, demonstrating their capacity for the arrest of growth and cellular respiration, impairment of RNA and intracellular protein levels at subinhibitory concentrations. In some instances, derivatives of MC4 were also shown to attenuate the production of staphylococcal virulence factors in vitro, such as the exoproteins α-toxin and Panton–Valentine Leukocidin (PVL). Trends observed from quantitative PCR assays suggested that nusbiarylins elicited these effects possibly by acting via but not limited to the modulation of global regulatory pathways, such as the agr regulon, which coordinates the expression of S. aureus genes associated with virulence. Our findings encourage the continued development of more potent compounds within this novel family of bacterial transcription inhibitors.

scholarly journals Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3788
Author(s):  
Karolina Witek ◽  
Gniewomir Latacz ◽  
Aneta Kaczor ◽  
Joanna Czekajewska ◽  
Ewa Żesławska ◽  
...  
Keyword(s):  
Structural Properties ◽  
Staphylococcus Epidermidis ◽  
Efflux Pump ◽  
Crystallographic Analysis ◽  
Synthetic Compounds ◽  
Structure Activity ◽  
Biological Studies ◽  
Erythromycin A ◽  
Sar Analysis

Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1–15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure–activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis. The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis. Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter.

Evidence for a central role of transcription in the timing mechanism of a circadian clock

1996 ◽  
Vol 271 (5) ◽  
pp. C1646-C1651 ◽  
Author(s):  
S. B. Khalsa ◽  
D. Whitmore ◽  
B. Bogart ◽  
G. D. Block
Keyword(s):  
Circadian Clock ◽  
Phase Shifts ◽  
High Concentration ◽  
Marine Mollusc ◽  
Transcription Inhibitors ◽  
Light Pulses ◽  
Pulse Experiment ◽  
Sensitive Phase ◽  
Transcription Inhibitor

The retinal circadian clock in the isolated in vitro eye of the marine mollusc Bulla gouldiana exhibits a phase-dependent requirement for transcription. The transcription-sensitive phase extends through most of the subjective day and therefore is substantially longer than the previously reported translation-sensitive phase. Lower concentrations of transcription inhibitors yield a significant dose-dependent lengthening of circadian period. Clock motion can be stopped by a high concentration of the transcription inhibitor 5,6-dichlorobenz-imidazole riboside (DRB) when applied during the sensitive phase; after withdrawal of the inhibitor, motion resumes from the phase at which it was stopped. In a double-pulse experiment, phase shifts to light pulses applied after DRB pulses, and not during the translation-sensitive phase, indicate that the inhibition of transcription has immediate effects on the phase of the clock. These data suggest that DRB-induced phase shifts are independent of translation, which implies that the rate of transcription itself plays a significant role in the mechanism underlying the generation of the circadian cycle.

Characterization of an Endogenous Transcription Inhibitor from Physarum polycephalum

1979 ◽  
Vol 34 (1-2) ◽  
pp. 76-86 ◽  
Author(s):  
Armin Hildebrandt ◽  
Rudolf Mengel
Keyword(s):  
Rna Polymerase ◽  
Physarum Polycephalum ◽  
Gel Filtration ◽  
In Vitro Transcription ◽  
Exchange Chromatography ◽  
Heat Stable ◽  
Transcription Inhibitor

Abstract A substance has been purified from isolated nuclei of Physarum polycephalum by equilibrium and velocity gradient centrifugations, ion exchange chromatography and gel filtration which has a high molecular weight, can be labeled in vivo with 32P, is heat stable and resistant to amylases, proteases, nucleases and phosphodiesterase but is sensitive to phosphatases or hydrolysis. This material consists of phospate and glycerol. It selectively inhibits in vitro transcription of RNA polymerases, predominantly the homologous enzyme A by binding to the enzyme. In the presence of this inhibitor of transcription a stable RNA polymerase-template complex cannot be formed. Binding to and inactivation of RNA polymerase is reversible at high ionic strength.

Scanning Electron Microscopy of Staphylococcus Epidermidis Adherence to Continuous Ambulatory Peritoneal Dialysis Catheters

1985 ◽  
Vol 43 ◽  
pp. 520-521
Author(s):  
William J. Lamoreaux ◽  
David L. Smalley ◽  
Larry M. Baddour ◽  
Alfred P. Kraus
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Staphylococcus Epidermidis ◽  
Sterile Saline ◽  
Intravascular Devices ◽  
Capd Patient ◽  
Scanning Electron

Infections associated with the use of intravascular devices have been documented and have been reported to be related to duration of catheter usage. Recently, Eaton et al. reported that Staphylococcus epidermidis may attach to silastic catheters used in continuous ambulatory peritoneal dialysis (CAPD) treatment. The following study presents findings using scanning electron microscopy (SEM) of S. epidermidis adherence to silastic catheters in an in vitro model. In addition, sections of polyvinyl chloride (PVC) dialysis bags were also evaluated by SEM.The S. epidermidis strain RP62A which had been obtained in a previous outbreak of coagulase-negative staphylococcal sepsis at local hospitals was used in these experiments. The strain produced surface slime on exposure to glucose, whereas a nonadherent variant RP62A-NA, which was also used in these studies, failed to produce slime. Strains were grown overnight on blood agar plates at 37°C, harvested from the surface and resuspended in sterile saline (0.85%), centrifuged (3,000 rpm for 10 minutes) and then washed twice in 0.1 M phosphate-buffered saline at pH 7.0. Organisms were resuspended at a concentration of ca. 106 CFU/ml in: a) sterile unused dianeal at 4.25% dextrose, b) sterile unused dianeal at 1.5% dextrose, c) sterile used dialysate previously containing 4.25% dextrose taken from a CAPD patient, and d) sterile used dialysate previously containing 1.5% dextrose taken from a CAPD patient.

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