Dual Effect of Synthetic Aminoglycosides: Antibacterial Activity against <i>Bacillus anthracis</i> and Inhibition of Anthrax Lethal Factor

Fridman, Micha; Belakhov, V. V.; Lee, Lac V.; Liang, Fu‐Sen; Wong, Chi‐Huey; Baasov, Timor

doi:10.1002/anie.200462003

Cited by 64 publications

(47 citation statements)

References 38 publications

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“…[2][3][4] The potential for bioterrorism and inadequate treatments for anthrax, especially at late stages of infection, have amplified interest in finding effective anthrax lethal factor inhibitors (LFi). Several approaches have led to the identification of a variety of LFi, [5][6][7][8] including library screening and optimization, [9,10] fragment-based NMR screening (BI-11B3, Figure 1), [11] mass-spectrometry-based screening, [12] and re-examination of inhibitors of other metallo-A C H T U N G T R E N N U N G proteinases and related hydroxamate-based compounds. [9,[13][14][15] An example of the latter class is the broad-spectrum matrix metalloproteinase inhibitor (MMPi) GM6001 (Figure 1), which was found to be an effective inhibitor of LF in vitro and in cell culture.…”

mentioning

confidence: 99%

Evaluation and Binding‐Mode Prediction of Thiopyrone‐Based Inhibitors of Anthrax Lethal Factor

et al. 2006

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mentioning

confidence: 99%

Evaluation and Binding‐Mode Prediction of Thiopyrone‐Based Inhibitors of Anthrax Lethal Factor

et al. 2006

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“…It is clear that the biological activity of aminoglycosides can arise from interactions with targets other than ribosomal RNA, as shown recently by their potent inhibition of Bacillus anthracis Lethal Factor protease activity (27). Future efforts should be focused on the detailed characterization of sequences identified in this work to identify new RNA motifs and their interactions with small-molecule ligands.…”

Section: Methodsmentioning

confidence: 84%

Evaluation of RNA-binding specificity of aminoglycosides with DNA microarrays

Liang¹,

Greenberg²,

Hammond

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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We have developed methods for using DNA array technology to probe the entire transcriptome to determine the RNA-binding specificity of ligands. Two methods were investigated. In the first method, the RNA-binding aminoglycoside antibiotic tobramycin was covalently linked to magnetic beads. The beads were bound to human liver mRNA and washed, and specifically bound RNA was eluted, amplified, and analyzed with DNA array technology. A small number of genes were found to bind specifically to the tobramycin beads. In the second method, the aminoglycoside ligand was added directly to the array hybridization reaction, and the signal was compared with a control experiment in the absence of ligand. The aminoglycosides were found to interfere with a small percentage of all hybridization events. These methods differ from traditional DNA array experiments in that the readout is a direct measure of the interaction between mRNA and a ligand, rather than an indirect measure of effect on expression. We expect that the results will lead to the discovery of new aminoglycosidebinding RNA motifs and may also have relevance toward understanding and overcoming the side effects observed with these antibiotics in the clinic. aminoglycoside-RNA interactionsA minoglycosides are among the most commonly used broadspectrum antibiotics in the clinic. Since the initial discovery of streptomycin in 1944, a series of aminoglycoside antibiotics, including kanamycin, neomycin B, gentamicin, and tobramycin have been successfully introduced as treatments for serious systemic infections and have been used for a variety of topical applications.The origin of the bactericidal activity of aminoglycosides has been extensively investigated and is due to binding to the bacterial ribosome (1). Aminoglycosides bind specifically to the 16S rRNA, near the mRNA decoding site. This binding decreases the fidelity of protein translation by lowering the energetic cost of a conformational transition in the ribosome that is required for the discrimination between near-cognate and cognate tRNAs (2-4). Interference with translation causes the production of erroneous proteins, and accumulation of mutant membrane proteins compromises the integrity of the bacterial envelope, which then allows the uptake of more aminoglycosides, resulting in further misreading and, eventually, cell lysis (5). Other aminoglycosides, such as apramycin and spectinomycin, act in a different mode by inhibiting the translocation process (6, 7).Under physiological conditions, aminoglycosides are cationic. The importance of electrostatic interactions in specific binding between aminoglycosides and their anionic RNA targets has been well established (8,9). Binding of aminoglycosides to nonribosomal RNAs may contribute to their potential therapeutic applications but also to the side effects that are observed for this class of compounds. Serious side effects, including ototoxicity and nephrotoxicity, have been reported and have limited the clinical use of aminoglycosides.Methods, such as surface plasm...

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“…However, much lower concentrations of polycationic compounds such as neomycin B are required to inhibit LF when assayed in this manner. At physiological salt concentration (150 mM KCl) the K i for neomycin B increases to around 60 M. Interestingly, among a series of neomycin B derivatives evaluated for inhibition of LF, a disulfide-linked dimeric analog could inhibit at physiological salt with a K i of 1 M [99]. Though this compound itself would be expected to convert to the less active monomeric species in the reducing environment of the cytosol, the potential for generating redox stable dimeric neomycin B analogs that maintain activity holds promise.…”

Section: Other Competitive Inhibitors Of Lfmentioning

confidence: 97%

“…This finding suggests that it might be possible to treat anthrax with a single agent that would act both as an antibiotic and anti-toxin. Indeed, among a series of neomycin B derivatives synthesized and tested, many (including the parent compound itself) could both inhibit LF in vitro and block growth of B. anthracis in culture [99]. Unfor- tunately, the high potency originally ascribed to neomycin B and its analogs appears to be sensitive to in vitro assay conditions, and the drug is unlikely to substantially inhibit LF in vivo.…”

Section: Other Competitive Inhibitors Of Lfmentioning

confidence: 99%

Discovery and Development of Anthrax Lethal Factor Metalloproteinase Inhibitors

Turk¹

2008

CPB

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Anthrax is caused by infection with Bacillus anthracis, a spore forming, rod-shaped, encapsulated gram positive bacteria. The disease manifests itself in distinct ways depending on the route of entry of infective bacterial spores: cutaneous, inhalational, and gastrointestinal. Though rare in humans, inhalational anthrax has become a major concern due to the capacity for spores to be weaponized. The limited success of antibiotic therapy has motivated investigation of complementary therapeutic strategies that target the bacteria's secreted toxin. The zinc-dependent metalloproteinase lethal factor (LF) is a critical component of anthrax toxin and an important potential target for small molecule drugs. In the past few years, a number of approaches have been taken to identify LF inhibitors, from generating conventional metal chelating substrate analogs to random screening of diverse compound libraries. These efforts have produced several different classes of specific nanomolar range inhibitors. Some compounds have fared well in animal models for anthrax toxemia and infection, and these inhibitors and their derivatives may form the basis for future therapies to treat the disease in humans.

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Dual Effect of Synthetic Aminoglycosides: Antibacterial Activity against Bacillus anthracis and Inhibition of Anthrax Lethal Factor

Cited by 64 publications

References 38 publications

Evaluation and Binding‐Mode Prediction of Thiopyrone‐Based Inhibitors of Anthrax Lethal Factor

Evaluation and Binding‐Mode Prediction of Thiopyrone‐Based Inhibitors of Anthrax Lethal Factor

Evaluation of RNA-binding specificity of aminoglycosides with DNA microarrays

Discovery and Development of Anthrax Lethal Factor Metalloproteinase Inhibitors

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