scholarly journals Single 23S rRNA mutations at the ribosomal peptidyl transferase centre confer resistance to valnemulin and other antibiotics inMycobacterium smegmatisby perturbation of the drug binding pocket

2009 ◽  
Vol 71 (5) ◽  
pp. 1218-1227 ◽  
Author(s):  
Katherine S. Long ◽  
Jacob Poehlsgaard ◽  
Lykke H. Hansen ◽  
Sven N. Hobbie ◽  
Erik C. Böttger ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Drug Binding ◽  
23S Rrna ◽  
Peptidyl Transferase ◽  
Peptidyl Transferase Centre

A base pair between tRNA and 23S rRNA in the peptidyl transferase centre of the ribosome

Nature ◽  
1995 ◽  
Vol 377 (6547) ◽  
pp. 309-314 ◽  
Author(s):  
Raymond R. Samaha ◽  
Rachel Green ◽  
Harry F. Noller
Keyword(s):  
Base Pair ◽  
23S Rrna ◽  
Peptidyl Transferase ◽  
Peptidyl Transferase Centre

scholarly journals Phylogenetic Sequence Variations in Bacterial rRNA Affect Species-Specific Susceptibility to Drugs Targeting Protein Synthesis

2011 ◽  
Vol 55 (9) ◽  
pp. 4096-4102 ◽  
Author(s):  
Subramanian Akshay ◽  
Mihai Bertea ◽  
Sven N. Hobbie ◽  
Björn Oettinghaus ◽  
Dimitri Shcherbakov ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Drug Susceptibility ◽  
Drug Binding ◽  
23S Rrna ◽  
Content Type ◽  
Sequence Variations ◽  
Binding Pockets ◽  
Species Specific ◽  
Peptidyltransferase Center ◽  
A Site

ABSTRACTAntibiotics targeting the bacterial ribosome typically bind to highly conserved rRNA regions with only minor phylogenetic sequence variations. It is unclear whether these sequence variations affect antibiotic susceptibility or resistance development. To address this question, we have investigated the drug binding pockets of aminoglycosides and macrolides/ketolides. The binding site of aminoglycosides is located within helix 44 of the 16S rRNA (A site); macrolides/ketolides bind to domain V of the 23S rRNA (peptidyltransferase center). We have used mutagenesis of rRNA sequences inMycobacterium smegmatisribosomes to reconstruct the different bacterial drug binding sites and to study the effects of rRNA sequence variations on drug activity. Our results provide a rationale for differences in species-specific drug susceptibility patterns and species-specific resistance phenotypes associated with mutational alterations in the drug binding pocket.

scholarly journals The Cfr rRNA Methyltransferase Confers Resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A Antibiotics

2006 ◽  
Vol 50 (7) ◽  
pp. 2500-2505 ◽  
Author(s):  
Katherine S. Long ◽  
Jacob Poehlsgaard ◽  
Corinna Kehrenberg ◽  
Stefan Schwarz ◽  
Birte Vester
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Agents ◽  
Susceptibility Testing ◽  
Drug Binding ◽  
Animal Origin ◽  
23S Rrna ◽  
Peptidyl Transferase ◽  
E Coli ◽  
Peptidyl Transferase Center ◽  
Drug Classes

ABSTRACT A novel multidrug resistance phenotype mediated by the Cfr rRNA methyltransferase is observed in Staphylococcus aureus and Escherichia coli. The cfr gene has previously been identified as a phenicol and lincosamide resistance gene on plasmids isolated from Staphylococcus spp. of animal origin and recently shown to encode a methyltransferase that modifies 23S rRNA at A2503. Antimicrobial susceptibility testing shows that S. aureus and E. coli strains expressing the cfr gene exhibit elevated MICs to a number of chemically unrelated drugs. The phenotype is named PhLOPSA for resistance to the following drug classes: Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics. Each of these five drug classes contains important antimicrobial agents that are currently used in human and/or veterinary medicine. We find that binding of the PhLOPSA drugs, which bind to overlapping sites at the peptidyl transferase center that abut nucleotide A2503, is perturbed upon Cfr-mediated methylation. Decreased drug binding to Cfr-methylated ribosomes has been confirmed by footprinting analysis. No other rRNA methyltransferase is known to confer resistance to five chemically distinct classes of antimicrobials. In addition, the findings described in this study represent the first report of a gene conferring transferable resistance to pleuromutilins and oxazolidinones.

scholarly journals A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jessica Knox ◽  
Nicolas Joly ◽  
Edmond M. Linossi ◽  
José A. Carmona-Negrón ◽  
Natalia Jura ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Developmental Delay ◽  
Small Molecule ◽  
Parasitic Nematode ◽  
Kinase Inhibitor ◽  
Binding Pocket ◽  
Drug Binding ◽  
Nematode Infection ◽  
Selective Inhibitors ◽  
C Elegans

AbstractOver one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.

Structure of a conserved RNA component of the peptidyl transferase centre

1997 ◽  
Vol 4 (10) ◽  
pp. 775-778 ◽  
Author(s):  
Elisabetta Viani Puglisi ◽  
Rachel Green ◽  
Harry F. Noller ◽  
Joseph D. Puglisi
Keyword(s):  
Peptidyl Transferase ◽  
Peptidyl Transferase Centre

scholarly journals Structural basis for subtype-specific inhibition of the P2X7 receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Akira Karasawa ◽  
Toshimitsu Kawate
Keyword(s):  
P2x7 Receptor ◽  
Hydrophobic Interactions ◽  
Binding Pocket ◽  
Drug Binding ◽  
Structural Basis ◽  
Atp Binding ◽  
Allosteric Site ◽  
Channel Opening ◽  
A Site ◽  
Novel Drug

The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases.

scholarly journals UV-induced modifications in the peptidyl transferase loop of 23S rRNA dependent on binding of the streptogramin B antibiotic, pristinamycin IA

RNA ◽  
1999 ◽  
Vol 5 (4) ◽  
pp. 585-595 ◽  
Author(s):  
BO T. PORSE ◽  
STANISLAV V. KIRILLOV ◽  
MARIANA J. AWAYEZ ◽  
ROGER A. GARRETT
Keyword(s):  
23S Rrna ◽  
Peptidyl Transferase
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