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Fluorescent Trimethylated Naphthyridine Derivative With An Aminoalkyl Side Chain As The Tightest Non-aminoglycoside Ligand For The Bacterial A-site RNA.
Y. Sato, Masafumi Rokugawa, S. Ito, Sayaka Yajima, H. Sugawara, N. Teramae, S. Nishizawa
Published 2018 · Chemistry, Medicine
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The bacterial ribosomal decoding region of the aminoacyl-tRNA site (A-site) is one of the most validated target RNAs for antibiotic agents. Although natural aminoglycosides are well-characterized A-site binding ligands, high off-target effects and the growing emergence of bacterial resistance against aminoglycosides limit their clinical use. To circumvent these concerns with the aminoglycoside family, non-aminoglycoside A-site binding ligands have great potential as novel antibiotics against bacterial infections. This work describes a new class of small heterocyclic ligands based on the 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND) structure for the bacterial (Escherichia coli) A-site. ATMND possessing an aminoethyl side chain is found to strongly and selectively bind to the internal loop of the A-site (Kd =0.44 μm; pH 7.0, I=0.06 m, 5 °C). Significantly, this ligand shows the tightest binding reported to date among non-aminoglycoside ligands. The binding study based on the thermodynamics and molecular modelling reveals key molecular interactions of ATMND-C2 -NH2 for high affinity to the A-site. This ligand is also demonstrated to be applicable to the fluorescence indicator displacement assay for assessing ligand/A-site interactions.
This paper references
Stereospecificity of aminoglycoside-ribosomal interactions.
D. H. Ryu (2002)
Interaction of antibiotics with functional sites in 16S ribosomal RNA
D. Moazed (1987)
2-Deoxystreptamine: central scaffold of aminoglycoside antibiotics.
G. F. Busscher (2005)
The Emerging Role of RNA as a Therapeutic Target for Small Molecules
Colleen M. Connelly (2016)
Incorporation of thio-pseudoisocytosine into triplex-forming peptide nucleic acids for enhanced recognition of RNA duplexes
G. Devi (2014)
SAR by MS: a ligand based technique for drug lead discovery against structured RNA targets.
E. Swayze (2002)
Small-molecule binding at an abasic site of DNA: strong binding of lumiflavin for improved recognition of thymine-related single nucleotide polymorphisms.
N. Sankaran (2009)
Discovery of aminoglycoside mimetics by NMR-based screening of Escherichia coli A-site RNA.
Liping Yu (2003)
Methods to enable the design of bioactive small molecules targeting RNA.
M. D. Disney (2014)
New trends in the use of aminoglycosides
M. Fosso (2014)
Optimization of the Alkyl Linker of TO Base Surrogate in Triplex-Forming PNA for Enhanced Binding to Double-Stranded RNA.
T. Sato (2017)
Origins of the large differences in stability of DNA and RNA helices: C-5 methyl and 2'-hydroxyl effects.
S. Wang (1995)
Ribosome-targeting antibiotics and mechanisms of bacterial resistance
D. Wilson (2013)
The Future of Aminoglycosides: The End or Renaissance?
Jacob L. Houghton (2010)
Fluorescent trimethyl-substituted naphthyridine as a ligand for C-C mismatch detection in CCG trinucleotide repeats.
Y. Sato (2011)
Once-daily dosing of aminoglycosides: review and recommendations for clinical practice.
C. D. Freeman (1997)
Thermodynamic analysis of ion effects on the binding and conformational equilibria of proteins and nucleic acids: the roles of ion association or release, screening, and ion effects on water activity.
M. Record (1978)
Molecular recognition of aminoglycoside antibiotics by ribosomal RNA and resistance enzymes: an analysis of x-ray crystal structures.
Q. Vicens (2003)
Influence of substituent modifications on the binding of 2-amino-1,8-naphthyridines to cytosine opposite an AP site in DNA duplexes: thermodynamic characterization
Y. Sato (2009)
Identification of a novel non-carbohydrate molecule that binds to the ribosomal A-site RNA.
S. P. Maddaford (2004)
A fluorescence-based screen for ribosome binding antibiotics.
Derrick A. Watkins (2013)
Structural hybridization of three aminoglycoside antibiotics yields a potent broad-spectrum bactericide that eludes bacterial resistance enzymes
J. P. Maianti (2016)
Crystal structure of paromomycin docked into the eubacterial ribosomal decoding A site.
Q. Vicens (2001)
RNA as a Drug Target: The Case of Aminoglycosides
Q. Vicens (2003)
Structure-Guided Discovery of Novel Aminoglycoside Mimetics as Antibacterial Translation Inhibitors
Y. Zhou (2005)
Dissecting the free energy of drug binding to DNA.
J. Chaires (1996)
High-throughput Assay for Quantification of Aminoglycoside–Ribosome Interaction
Shun Yamashita (2016)
Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics
A. Carter (2000)
Monitoring molecular recognition of the ribosomal decoding site.
S. Shandrick (2004)
A modified fluorescent intercalator displacement assay for RNA ligand discovery.
P. N. Asare-Okai (2011)
Ribosomal RNA and translation.
H. Noller (1991)
Interactions of a small RNA with antibiotic and RNA ligands of the 30S subunit
P. Purohit (1994)
Kinetic and thermodynamic analysis of triplex formation between peptide nucleic acid and double-stranded RNA.
T. Sato (2018)
Use of 2-aminopurine as a fluorescent tool for characterizing antibiotic recognition of the bacterial rRNA A-site.
C. M. Barbieri (2007)
Strong and selective binding of amiloride to an abasic site in RNA duplexes: thermodynamic characterization and microRNA detection.
Y. Sato (2012)
Effect of an alkyl amino group on the binding of 1,8-naphthyridines to AP site-containing DNA duplexes.
Toshiki Ichihashi (2008)
A high-throughput fluorescence screen to monitor the specific binding of antagonists to RNA targets.
K. Hamasaki (1998)
Enhancement of the binding ability of a ligand for nucleobase recognition by introducing a methyl group.
Q. Dai (2006)
Specificity of aminoglycoside binding to RNA constructs derived from the 16S rRNA decoding region and the HIV-RRE activator region.
Y. Wang (1997)
Conformational constraint as a means for understanding RNA-aminoglycoside specificity.
K. Blount (2005)
Probing structure and dynamics of DNA with 2-aminopurine: effects of local environment on fluorescence.
E. Rachofsky (2001)
Alloxazine as a ligand for selective binding to adenine opposite AP sites in DNA duplexes and analysis of single-nucleotide polymorphisms.
Burki Rajendar (2008)
Targeting RNA with small molecules.
J. Thomas (2008)
The bacterial and mitochondrial ribosomal A-site molecular switches possess different conformational substates
J. Kondo (2008)
Triplex-Forming Peptide Nucleic Acid Probe Having Thiazole Orange as a Base Surrogate for Fluorescence Sensing of Double-stranded RNA.
T. Sato (2016)
Short peptide nucleic acids bind strongly to homopurine tract of double helical RNA at pH 5.5.
Ming Li (2010)
Non-basic histamine H1-antagonists. I: Synthesis and biological evaluation of some substituted 2-(2-pyridylaminoalkylamino) pyrimidones and related compounds
R. Ife (1989)
Thermodynamics of aminoglycoside-rRNA recognition: the binding of neomycin-class aminoglycosides to the A site of 16S rRNA.
Malvika Kaul (2002)
Thermodynamics of aminoglycoside-rRNA recognition.
D. S. Pilch (2003)
Molecular insights into aminoglycoside action and resistance.
S. Magnet (2005)
Probing the Specificity of Aminoglycoside−Ribosomal RNA Interactions with Designed Synthetic Analogs
P. Alper (1998)
Base stacking and molecular polarizability: effect of a methyl group in the 5-position of pyrimidines.
L. Sowers (1987)
Waves of resistance: Staphylococcus aureus in the antibiotic era
H. Chambers (2009)
Ratiometric fluorescent signaling of small molecule, environmentally sensitive dye conjugates for detecting single-base mutations in DNA.
C. Wang (2012)
A structure-based strategy to identify new molecular scaffolds targeting the bacterial ribosomal A-site.
N. Foloppe (2004)
Structure-activity studies on the fluorescent indicator in a displacement assay for the screening of small molecules binding to RNA.
S. Umemoto (2012)
2-Aminopurine fluorescence studies of base stacking interactions at abasic sites in DNA: metal-ion and base sequence effects.
J. Stivers (1998)
Red-emissive triplex-forming PNA probes carrying cyanine base surrogates for fluorescence sensing of double-stranded RNA.
T. Chiba (2017)
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Y. Sato (2019)
Trimethine cyanine dyes as deep-red fluorescent indicators with high selectivity to the internal loop of the bacterial A-site RNA.
Y. Sato (2019)
Fluorescent indicator displacement assays to identify and characterize small molecule interactions with RNA.
Sarah L. Wicks (2019)
Small molecule-PNA oligomer conjugates for rRNA A-site at neutral pH for FID assays.
En Ting Tabitha Lee (2020)