A New Class of Bacterial RNA Polymerase Inhibitor Affects Nucleotide Addition

Science ◽  
2003 ◽  
Vol 302 (5645) ◽  
pp. 650-654 ◽  
Author(s):  
I. Artsimovitch
Keyword(s):  
Rna Polymerase ◽  
New Class ◽  
Bacterial Rna ◽  
Nucleotide Addition ◽  
Polymerase Inhibitor

Computer-aided structural and molecular insights into the mechanisms by which Pseudouridimycin (PUM) disrupts cleft extension in bacterial RNA polymerase to block DNA entry and exit

2020 ◽  
Vol 17 ◽  
Author(s):  
Ali H. Rabbad ◽  
Fisayo A. Olotu ◽  
Mahmoud E. Soliman
Keyword(s):  
Rna Polymerase ◽  
Bacterial Infections ◽  
Entry And Exit ◽  
Dynamic Binding ◽  
Binding Behavior ◽  
Bacterial Rna ◽  
Nucleotide Addition ◽  
Switch Regions ◽  
Cleft Extension ◽  
Key Residues

Background: The ability of Pseudouridimycin (PUM) to occupy the nucleotide addition site of bacterial RNA Polymerase (RNAP) underlies its inhibitory potency as previously reported. PUM has gained high research interest as a broad-spectrum nucleoside analog that has demonstrated exciting potentials in treating drug-resistant bacterial infections. Objective: Herein, we identified, for the first time, a novel complementary mechanism by which PUM elicits its inhibitory effects on bacterial RNAP. Methods: The dynamic binding behavior of PUM to bacterial RNAP was studied using various dynamic analyses approaches. Results and Discussion: Findings revealed that in addition to occupying the nucleotide addition site, PUM also interrupts the unimpeded entry and exit of DNA by reducing the mechanistic extension of the RNAP cleft and perturbing the primary conformations of the switch regions. Moreover, PUM binding reduced the distances between key residues in the β and β’ subunits that extend to accommodate the DNA. Conclusion: This study’s findings present structural insights that would contribute to the structure-based design of potent and selective PUM inhibitors.

scholarly journals Ribosomal RNA degradation induced by the bacterial RNA polymerase inhibitor rifampicin.

RNA ◽  
2021 ◽  
pp. rna.078776.121
Author(s):  
Lina Hamouche ◽  
Leonora Poljak ◽  
Agamemnon J. Carpousis
Keyword(s):  
Rna Polymerase ◽  
Ribosomal Rna ◽  
Rna Degradation ◽  
Bacterial Rna ◽  
Polymerase Inhibitor

scholarly journals New Insights into the Bacterial RNA Polymerase Inhibitor CBR703 as a Starting Point for Optimization as an Anti-Infective Agent

2014 ◽  
Vol 58 (7) ◽  
pp. 4242-4245 ◽  
Author(s):  
Weixing Zhu ◽  
Jörg Haupenthal ◽  
Matthias Groh ◽  
Michelle Fountain ◽  
Rolf W. Hartmann
Keyword(s):  
Rna Polymerase ◽  
Biofilm Formation ◽  
Mammalian Cells ◽  
Antibacterial Agents ◽  
Antibacterial Activities ◽  
Bacterial Rna ◽  
Starting Point ◽  
Polymerase Inhibitor ◽  
Derivatives Of ◽  
Infective Agent

ABSTRACTCBR703 was reported to inhibit bacterial RNA polymerase (RNAP) and biofilm formation, considering it to be a good candidate for further optimization. While synthesized derivatives of CBR703 did not result in more-active RNAP inhibitors, we observed promising antibacterial activities. These again correlated with a significant cytotoxicity toward mammalian cells. Furthermore, we suspect the promising effects on biofilm formation to be artifacts. Consequently, this class of compounds can be considered unattractive as antibacterial agents.

Total Synthesis of the Bacterial RNA Polymerase Inhibitor Ripostatin B

2012 ◽  
Vol 124 (14) ◽  
pp. 3461-3465 ◽  
Author(s):  
Florian Glaus ◽  
Karl-Heinz Altmann
Keyword(s):  
Rna Polymerase ◽  
Total Synthesis ◽  
Bacterial Rna ◽  
Polymerase Inhibitor

scholarly journals Trigger loop dynamics can explain stimulation of intrinsic termination by bacterial RNA polymerase without terminator hairpin contact

2017 ◽  
Vol 114 (44) ◽  
pp. E9233-E9242 ◽  
Author(s):  
Ananya Ray-Soni ◽  
Rachel A. Mooney ◽  
Robert Landick
Keyword(s):  
Rna Polymerase ◽  
Conformational Changes ◽  
Dna Sequences ◽  
Time Window ◽  
Kinetic Assay ◽  
Termination Rate ◽  
Trigger Loop ◽  
Bacterial Rna ◽  
Nucleotide Addition ◽  
Addition Rate

In bacteria, intrinsic termination signals cause disassembly of the highly stable elongating transcription complex (EC) over windows of two to three nucleotides after kilobases of RNA synthesis. Intrinsic termination is caused by the formation of a nascent RNA hairpin adjacent to a weak RNA−DNA hybrid within RNA polymerase (RNAP). Although the contributions of RNA and DNA sequences to termination are largely understood, the roles of conformational changes in RNAP are less well described. The polymorphous trigger loop (TL), which folds into the trigger helices to promote nucleotide addition, also is proposed to drive termination by folding into the trigger helices and contacting the terminator hairpin after invasion of the hairpin in the RNAP main cleft [Epshtein V, Cardinale CJ, Ruckenstein AE, Borukhov S, Nudler E (2007) Mol Cell 28:991–1001]. To investigate the contribution of the TL to intrinsic termination, we developed a kinetic assay that distinguishes effects of TL alterations on the rate at which ECs terminate from effects of the TL on the nucleotide addition rate that indirectly affect termination efficiency by altering the time window in which termination can occur. We confirmed that the TL stimulates termination rate, but found that stabilizing either the folded or unfolded TL conformation decreased termination rate. We propose that conformational fluctuations of the TL (TL dynamics), not TL-hairpin contact, aid termination by increasing EC conformational diversity and thus access to favorable termination pathways. We also report that the TL and the TL sequence insertion (SI3) increase overall termination efficiency by stimulating pausing, which increases the flux of ECs into the termination pathway.

Synthesis of Streptolydigin, a Potent Bacterial RNA Polymerase Inhibitor

2010 ◽  
Vol 132 (41) ◽  
pp. 14394-14396 ◽  
Author(s):  
Sergey V. Pronin ◽  
Sergey A. Kozmin
Keyword(s):  
Rna Polymerase ◽  
Bacterial Rna ◽  
Polymerase Inhibitor
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