scholarly journals Singly Modified Amikacin and Tobramycin Derivatives Show Increased rRNA A-Site Binding and Higher Potency against Resistant Bacteria

ChemMedChem ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. 2164-2171 ◽  
Author(s):  
Richard J. Fair ◽  
Lisa S. McCoy ◽  
Mary E. Hensler ◽  
Bernice Aguilar ◽  
Victor Nizet ◽  
...  
Keyword(s):  
Resistant Bacteria ◽  
A Site ◽  
Site Binding

scholarly journals pH-sensitivity of the ribosomal peptidyl transfer reaction dependent on the identity of the A-site aminoacyl-tRNA

2010 ◽  
Vol 108 (1) ◽  
pp. 79-84 ◽  
Author(s):  
Magnus Johansson ◽  
Ka-Weng Ieong ◽  
Stefan Trobro ◽  
Peter Strazewski ◽  
Johan Åqvist ◽  
...  
Keyword(s):  
Ph Value ◽  
Ph Dependence ◽  
Peptide Bond ◽  
Bulk Solution ◽  
Peptide Bond Formation ◽  
Transfer Rates ◽  
Peptidyl Transfer ◽  
A Site ◽  
Rate Limiting ◽  
Site Binding

We studied the pH-dependence of ribosome catalyzed peptidyl transfer from fMet-tRNAfMet to the aa-tRNAs Phe-tRNAPhe, Ala-tRNAAla, Gly-tRNAGly, Pro-tRNAPro, Asn-tRNAAsn, and Ile-tRNAIle, selected to cover a large range of intrinsic pKa-values for the α-amino group of their amino acids. The peptidyl transfer rates were different at pH 7.5 and displayed different pH-dependence, quantified as the pH-value, , at which the rate was half maximal. The -values were downshifted relative to the intrinsic pKa-value of aa-tRNAs in bulk solution. Gly-tRNAGly had the smallest downshift, while Ile-tRNAIle and Ala-tRNAAla had the largest downshifts. These downshifts correlate strongly with molecular dynamics (MD) estimates of the downshifts in pKa-values of these aa-tRNAs upon A-site binding. Our data show the chemistry of peptide bond formation to be rate limiting for peptidyl transfer at pH 7.5 in the Gly and Pro cases and indicate rate limiting chemistry for all six aa-tRNAs.

scholarly journals Influence of Linker Length and Composition on Enzymatic Activity and Ribosomal Binding of Neomycin Dimers

2015 ◽  
Vol 59 (7) ◽  
pp. 3899-3905 ◽  
Author(s):  
Derrick Watkins ◽  
Sunil Kumar ◽  
Keith D. Green ◽  
Dev P. Arya ◽  
Sylvie Garneau-Tsodikova
Keyword(s):  
Enzymatic Activity ◽  
Aminoglycoside Antibiotics ◽  
Substantial Decrease ◽  
Selective Binding ◽  
Linker Length ◽  
Neomycin B ◽  
A Site ◽  
Site Binding

ABSTRACTThe human and bacterial A site rRNA binding as well as the aminoglycoside-modifying enzyme (AME) activity against a series of neomycin B (NEO) dimers is presented. The data indicate that by simple modifications of linker length and composition, substantial differences in rRNA selectivity and AME activity can be obtained. We tested five different AMEs with dimeric NEO dimers that were tethered via triazole, urea, and thiourea linkages. We show that triazole-linked dimers were the worst substrates for most AMEs, with those containing the longer linkers showing the largest decrease in activity. Thiourea-linked dimers that showed a decrease in activity by AMEs also showed increased bacterial A site binding, with one compound (compound 14) even showing substantially reduced human A site binding. The urea-linked dimers showed a substantial decrease in activity by AMEs when a conformationally restrictive phenyl linker was introduced. The information learned herein advances our understanding of the importance of the linker length and composition for the generation of dimeric aminoglycoside antibiotics capable of avoiding the action of AMEs and selective binding to the bacterial rRNA over binding to the human rRNA.

scholarly journals Ensifer, Phyllobacterium and Rhizobium species occupy nodules of Medicago sativa (alfalfa) and Melilotus alba (sweet clover) grown at a Canadian site without a history of cultivation

Microbiology ◽  
2010 ◽  
Vol 156 (2) ◽  
pp. 505-520 ◽  
Author(s):  
E. S. P. Bromfield ◽  
J. T. Tambong ◽  
S. Cloutier ◽  
D. Prévost ◽  
G. Laguerre ◽  
...  
Keyword(s):  
23S Rrna ◽  
Resistant Bacteria ◽  
Sweet Clover ◽  
Mineral Salts ◽  
Medicago Lupulina ◽  
Protein Encoding ◽  
History Of ◽  
Macroptilium Atropurpureum ◽  
A Site ◽  
Multiple Antibiotics

Phage-resistant and -susceptible bacteria from nodules of alfalfa and sweet clover, grown at a site without a known history of cultivation, were identified as diverse genotypes of Ensifer, Rhizobium and Phyllobacterium species based on sequence analysis of ribosomal (16S and 23S rRNA) and protein-encoding (atpD and recA) genes, Southern hybridization/RFLP and a range of phenotypic characteristics. Among phage-resistant bacteria, one genotype of Rhizobium sp. predominated on alfalfa (frequency ∼68 %) but was recovered infrequently (∼1 %) from sweet clover. A second genotype was isolated infrequently only from alfalfa. These genotypes fixed nitrogen poorly in association with sweet clover and Phaseolus vulgaris, but were moderately effective with alfalfa. They produced a near-neutral reaction on mineral salts agar containing mannitol, which is atypical of the genus Rhizobium. A single isolate of Ensifer sp. and two of Phyllobacterium sp. were recovered only from sweet clover. All were highly resistant to multiple antibiotics. Phylogenetic analysis indicated that Ensifer sp. strain T173 is closely related to, but separate from, the non-symbiotic species ‘Sinorhizobium morelense’. Strain T173 is unique in that it possesses a 175 kb symbiotic plasmid and elicits ineffective nodules on alfalfa, sweet clover, Medicago lupulina and Macroptilium atropurpureum. The two Phyllobacterium spp. were non-symbiotic and probably represent bacterial opportunists. Three genotypes of E. meliloti that were symbiotically effective with alfalfa and sweet clover were encountered infrequently. Among phage-susceptible isolates, two genotypes of E. medicae were encountered infrequently and were highly effective with alfalfa, sweet clover and Medicago polymorpha. The ecological and practical implications of the findings are discussed.

scholarly journals Antimicrobial Activity, AME Resistance, and A-Site Binding Studies of Anthraquinone–Neomycin Conjugates

2017 ◽  
Vol 3 (3) ◽  
pp. 206-215 ◽  
Author(s):  
Natalya N. Degtyareva ◽  
Changjun Gong ◽  
Sandra Story ◽  
Nathanael S. Levinson ◽  
Adegboyega K. Oyelere ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Binding Studies ◽  
A Site ◽  
Site Binding

scholarly journals Histidine 197 in Release Factor 1 Is Essential for A Site Binding and Peptide Release

Biochemistry ◽  
2010 ◽  
Vol 49 (43) ◽  
pp. 9385-9390 ◽  
Author(s):  
Andrew Field ◽  
Byron Hetrick ◽  
Merrill Mathew ◽  
Simpson Joseph
Keyword(s):  
Release Factor ◽  
Peptide Release ◽  
A Site ◽  
Site Binding

scholarly journals METTL3-Mediated DLGAP1 Antisense RNA 2 Promotes Gastric Cancer Tumorigenesis Through Facilitating C-Myc-Dependent Warburg Effect

2021 ◽  
Author(s):  
Changshun Yang ◽  
Yu Zhang ◽  
Xuefei Cheng ◽  
Weihua Li
Keyword(s):  
Gastric Cancer ◽  
Antisense Rna ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Dependent Manner ◽  
Rna Immunoprecipitation ◽  
The Stability ◽  
A Site ◽  
Rip Assay ◽  
Site Binding

Abstract Background The critical roles of N6-methyladenosine (m6A) modification have been demonstrated by more and more evidence. However, the cross-talking of m6A and long non-coding RNAs (lncRNAs) in gastric cancer (GC) tumorigenesis is still unclear. Here, our work focused on the functions and molecular mechanism of m6A-modified lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) in GC. Methods LncRNA expression profile data was derived from GEO. M6A profile was screened using Methylated RNA immunoprecipitation sequencing (MeRIP-Seq). The metabolism assays were conducted using quantitative analysis of glucose, lactate, ATP and extracellular acidification rate (ECAR). The m6A level of specific RNA was identified using MeRIP-qPCR. The molecular interaction was detected using RIP assay. Results Microarray analysis found that lncRNA DLGAP1-AS2 up-regulated in GC cells. Clinical data showed that DLGAP1-AS2 high-expression was correlated with advanced pathological stage and poor prognosis. Functionally, DLGAP1-AS2 promoted the Warburg effect (aerobic glycolysis) and knockdown of DLGAP1-AS2 suppressed the tumor growth of GC cells. Mechanistically, m6A methyltransferase METTL3 enhanced the stability of DLGAP1-AS2 via m6A site binding. Moreover, DLGAP1-AS2 interacted with YTHDF1 to enhance the stability of c-Myc mRNA through DLGAP1-AS2/m6A/YTHDF1/c-Myc mRNA. Conclusions In conclusion, our work indicates the functions of m6A-modified DLGAP1-AS2 in the GC aerobic glycolysis, disclosing a potential m6A-dependent manner for GC treatment.

scholarly journals High incidence of selenite-resistant bacteria from a site polluted with selenium.

1987 ◽  
Vol 53 (1) ◽  
pp. 185-188 ◽  
Author(s):  
G A Burton ◽  
T H Giddings ◽  
P DeBrine ◽  
R Fall
Keyword(s):  
Resistant Bacteria ◽  
High Incidence ◽  
A Site

scholarly journals Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates

2019 ◽  
Vol 163 ◽  
pp. 381-393 ◽  
Author(s):  
Sandra Story ◽  
Michael J. Skriba ◽  
Krishnagopal Maiti ◽  
Nihar Ranjan ◽  
Natalya N. Degtyareva ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Aminoglycoside Resistance ◽  
A Site ◽  
Site Binding

scholarly journals tRNA tKUUU, tQUUG, and tEUUC wobble position modifications fine-tune protein translation by promoting ribosome A-site binding

2013 ◽  
Vol 110 (30) ◽  
pp. 12289-12294 ◽  
Author(s):  
V. A. N. Rezgui ◽  
K. Tyagi ◽  
N. Ranjan ◽  
A. L. Konevega ◽  
J. Mittelstaet ◽  
...  
Keyword(s):  
Protein Translation ◽  
Wobble Position ◽  
A Site ◽  
Fine Tune ◽  
Site Binding

scholarly journals Tigecycline – how powerful is it in the fight against antibiotic-resistant bacteria?

Medicina ◽  
2010 ◽  
Vol 46 (4) ◽  
pp. 240 ◽  
Author(s):  
Vaida Šeputienė ◽  
Justas Povilonis ◽  
Julija Armalytė ◽  
Kęstutis Sužiedėlis ◽  
Alvydas Pavilonis ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Bacterial Species ◽  
Tetracycline Resistance ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Application Development ◽  
Cellular Mechanisms ◽  
Development Of Resistance ◽  
Elongation Step ◽  
A Site

Tigecycline is a semisynthetic analogue of earlier tetracyclines and represents the first member of a novel class of antimicrobials – glycylcyclines – recently approved for clinical use. It is active against a broad range of gram-negative and gram-positive bacterial species including clinically important multidrug-resistant nosocomial and community-acquired bacterial pathogens. The exact molecular basis of tigecycline action is not clear at present, although similarly to the tetracyclines, it has been shown to inhibit the translation elongation step by binding to the ribosome 30S subunit and preventing aminoacylated tRNAs to accommodate in the ribosomal A site. Importantly, tigecycline overcomes the action of ribosomal protection proteins and is not a substrate for tetracycline efflux pumps of most bacteria – well-known and prevalent cellular mechanisms of microbial tetracycline resistance. The present review summarizes current knowledge on the molecular mechanism of the tigecycline action, antibacterial activity against various bacteria, clinical application, development of resistance to glycylcyclines.

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