Structure-Guided Discovery of Novel Aminoglycoside Mimetics as Antibacterial Translation Inhibitors

ABSTRACT We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.

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A NewIn VivoModel System to Assess the Toxicity of Semiconductor Nanocrystals

International Journal of Biomaterials ◽

10.1155/2011/792854 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Angela Tino ◽

Alfredo Ambrosone ◽

Lucia Mattera ◽

Valentina Marchesano ◽

Andrei Susha ◽

...

Keyword(s):

Semiconductor Nanocrystals ◽

Minimal Risk ◽

The Novel ◽

Toxicological Evaluation ◽

Hydra Vulgaris ◽

Population Growth Rates ◽

Single Structure

In the emerging area of nanotechnology, a key issue is related to the potential impacts of the novel nanomaterials on the environment and human health, so that this technology can be used with minimal risk. Specifically designed to combine on a single structure multipurpose tags and properties, smart nanomaterials need a comprehensive characterization of both chemicophysical properties and adequate toxicological evaluation, which is a challenging endeavour; thein vitrotoxicity assays that are often employed for nanotoxicity assessments do not accurately predictin vivoresponse. To overcome these limitations and to evaluate toxicity characteristics of cadmium telluride quantum dots in relation to surface coatings, we have employed the freshwater polypHydra vulgarisas a model system. We assessedin vivoacute and sublethal toxicity by scoring for alteration of morphological traits, population growth rates, and influence on the regenerative capabilities providing new investigation clues for nanotoxicology purposes.

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Characterization of Novel Antimicrobial Peptoids

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.6.1429 ◽

1999 ◽

Vol 43 (6) ◽

pp. 1429-1434 ◽

Cited By ~ 87

Author(s):

Bob Goodson ◽

Anton Ehrhardt ◽

Simon Ng ◽

John Nuss ◽

Kirk Johnson ◽

...

Keyword(s):

Antibacterial Activities ◽

Membrane Disruption ◽

Infection Model ◽

Gram Negative Bacteria ◽

Positional Isomers ◽

Bacterial Growth Inhibition ◽

Alpha Carbon

ABSTRACT Peptoids differ from peptides in that peptoids are composed of N-substituted rather than alpha-carbon-substituted glycine units. In this paper we report the in vitro and in vivo antibacterial activities of several antibacterial peptoids discovered by screening combinatorial chemistry libraries for bacterial growth inhibition. In vitro, the peptoid CHIR29498 and some of its analogues were active in the range of 3 to 12 μg/ml against a panel of gram-positive and gram-negative bacteria which included isolates which were resistant to known antibiotics. Peptoid antimicrobial activity againstStaphylococcus aureus was rapid, bactericidal, and independent of protein synthesis. β-Galactosidase and propidium iodide leakage assays indicated that the membrane is the most likely target of activity. Positional isomers of an active peptoid were also active, consistent with a mode of action, such as membrane disruption, that does not require a specific fit between the molecule and its target. In vivo, CHIR29498 protected S. aureus-infected mice in a simple infection model.

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Functional Characterization of the Novel Neuronal Nicotinic Acetylcholine Receptor Ligand GTS-21 In Vitro and In Vivo

Pharmacology Biochemistry and Behavior ◽

10.1016/s0091-3057(96)00354-1 ◽

1997 ◽

Vol 57 (1-2) ◽

pp. 231-241 ◽

Cited By ~ 136

Author(s):

Clark A Briggs ◽

David J Anderson ◽

Jorge D Brioni ◽

Jerry J Buccafusco ◽

Michael J Buckley ◽

...

Keyword(s):

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Functional Characterization ◽

Neuronal Nicotinic Acetylcholine Receptor ◽

The Novel ◽

Receptor Ligand ◽

Nicotinic Acetylcholine

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Antimicrobial and Drug Releasing Studies of Novel Acrylate Polymer based on Triazine

Asian Journal of Chemistry ◽

10.14233/ajchem.2021.23018 ◽

2021 ◽

Vol 33 (11) ◽

pp. 2707-2714

Author(s):

P. Uma ◽

J. Suresh ◽

Revathi Selvaraj ◽

A. Arun

Keyword(s):

Average Molecular Weight ◽

Synthesis And Characterization ◽

Gram Negative Bacteria ◽

The Novel ◽

Acrylate Monomer ◽

Weight Average Molecular Weight ◽

Drug Molecules ◽

Acrylate Polymer

This work is focused on the synthesis and characterization of versatile acrylate polymer of chalcone based triazine for their antibacterial activity and cumulative drug release behaviour studies. The novel acrylate monomer 4-(3-(4-((4-(4-(3-(4-((7-chloroquinolin-4-yl)amino)-phenyl)-3-oxoprop-1-en-1- yl)phenoxy)-6-((4-nitrophenyl)amino)-1,3,5-triazin-2-yl)oxy)phenyl)-3-oxoprop-1-en-1- yl)phenylacrylate (SCP) is from novel chalcone and acryloyl chloride. Homo and copolymers of SCP were prepared using acrylic acid and hydroxyethyl acrylate. Physical characterization confirms the formation of the above compounds. Prepared drug molecules possess chalcone moiety as well as quinoline so it has the greater effect to inhibit the growth of the Gram-negative bacteria (15.63 ± 0.4 μg/mL) was confirmed by MIC method. The weight average molecular weight of the polymer is 10,000 g/mol. The polymer decomposes at 325 ºC. Drug releasing in vitro behaviour of the synthesized drug is controlled by the nature of comonomer, pH and the temperature.

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Novel Antiplasmodial Agents from Christia vespertilionis

Natural Product Communications ◽

10.1177/1934578x1300801123 ◽

2013 ◽

Vol 8 (11) ◽

pp. 1934578X1300801 ◽

Cited By ~ 3

Author(s):

Harish C. Upadhyay ◽

Brijesh S. Sisodia ◽

Harveer S. Cheema ◽

Jyoti Agrawal ◽

Anirban Pal ◽

...

Keyword(s):

Antimalarial Activity ◽

Complete Suppression ◽

The Novel ◽

Aqueous Methanol ◽

Isolation And Characterization ◽

First Time ◽

Detailed Chemical

The roots, leaves and stems of Christia vespertilionis were separately and successively extracted with methanol and aqueous-methanol (1:4, v/v) and were evaluated in vitro for their antiplasmodial potential against Plasmodium falciparum NF-54. The aqueous-methanolic stem (AS) extract was the most active (IC50 7.5 μg/mL) followed by the methanolic leaf (ML) extract (IC50 32.0 μg/mL). The in vivo antimalarial activity of the combined plant extract of C. vespertilionis was also assessed in P. berghei infected mice, which showed 87.8% suppression of parasitaemia as compared with complete suppression by chloroquine on day 8. Finally, detailed chemical investigation of C. vespertilionis resulted in the isolation and characterization of fifteen compounds (1–15), of which two (1 and 4) are being reported for the first time from nature. The novel compound 1 possesses potent antiplasmodial activity (IC50 = 9.0 μg/mL).

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In vitro and in vivo characterization of the novel GABAB receptor positive allosteric modulator, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE)

Neuropharmacology ◽

10.1016/j.neuropharm.2011.06.024 ◽

2011 ◽

Vol 61 (5-6) ◽

pp. 957-966 ◽

Cited By ~ 20

Author(s):

Elisabetta Perdona’ ◽

Vivian J.A. Costantini ◽

Michela Tessari ◽

Prisca Martinelli ◽

Corrado Carignani ◽

...

Keyword(s):

Gabab Receptor ◽

Allosteric Modulator ◽

The Novel ◽

Positive Allosteric Modulator ◽

In Vivo Characterization

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Do mycoplasmas cause human cancer?

Canadian Journal of Microbiology ◽

10.1139/w01-053 ◽

2001 ◽

Vol 47 (8) ◽

pp. 691-697 ◽

Cited By ~ 28

Author(s):

Nevio Cimolai

Keyword(s):

Tissue Culture ◽

Molecular Mechanisms ◽

Human Cancer ◽

Epidemiological Studies ◽

Respiratory Pathogen ◽

The Novel ◽

The 1960S ◽

In Vitro Data

A linkage between mycoplasmas and malignancy was mainly proposed in the 1960s when human-associated mycoplasmas were becoming of interest given the novel characterization of the human respiratory pathogen Mycoplasma pneumoniae. Associations with leukemia and other malignancies, however, were largely ascribed to tissue-culture contamination, which is now recognized as a significant potential problem in molecular biology circles. A few epidemiological studies, however, continue to raise concern over such a linkage. As well, in vitro data have demonstrated the potential for some mycoplasmas to induce karyotypic changes and malignant transformation during chronic tissue-culture infestation. As cellular and molecular mechanisms for such transformation become studied, a resurgence of interest in this area is inevitable. A role for mycoplasmas in malignancy of any sort is conjectural, but there remains a need to continue with focussed epidemiological and laboratory investigations.Key words: mycoplasma, cancer, oncogenesis, leukemia.

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In Vitro and In Vivo Characterization of the Novel Opioid Antagonists NAP and NAQ

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.887.4 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Amanda Braithwaite ◽

Denise Giuvelis ◽

John Streicher ◽

Yunyun Yuan ◽

Yan Zhang ◽

...

Keyword(s):

The Novel ◽

Opioid Antagonists ◽

In Vivo Characterization

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Characterization of the Nonconserved hpaB-hrpF Region in the hrp Pathogenicity Island from Xanthomonas campestris pv. vesicatoria

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-20-9-1063 ◽

2007 ◽

Vol 20 (9) ◽

pp. 1063-1074 ◽

Cited By ~ 32

Author(s):

Daniela Büttner ◽

Laurent Noël ◽

Johannes Stuttmann ◽

Ulla Bonas

Keyword(s):

Type Iii Secretion ◽

Xanthomonas Campestris ◽

Effector Proteins ◽

The Novel ◽

Phytopathogenic Bacterium ◽

Lytic Transglycosylase ◽

Hrp Genes

The interaction of the gram-negative phytopathogenic bacterium Xanthomonas campestris pv. vesicatoria with its host plants pepper and tomato is mediated by a type III secretion (T3S) system that translocates bacterial effector proteins into the plant cell. The T3S system is encoded by the chromosomal hrp (hypersensitive response and pathogenicity) gene cluster. Here, we report on the analysis of the hpaB-hrpF region, which encodes the novel virulence factor HpaE, the effector protein XopF1, and two proteins with unknown functions, HpaD and HpaI. Promoter and transcript analyses revealed that the corresponding genes are coexpressed with the hrp genes and that hpaD, hpaI, and xopF1 form a novel operon. In vitro and in vivo assays showed that the efficient T3S and translocation of XopF1 depends on the global T3S chaperone HpaB and the putative lytic transglycosylase HpaH, which specifically contributes to the secretion of a certain set of effectors. Taken together, our data suggest that the efficient secretion of effector proteins in X. campestris pv. vesicatoria requires the contribution of several different Hpa proteins.

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