The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Martin N. Martinov - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity
2016Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:Without quantum theory any understanding of molecular interactions is incomplete. In prin-cipal, chemistry, and even biology, can be fully derived from non-relativistic quantum me-chanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantummethods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo he-patic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four com-pounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, Cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (ove
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Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity.
PLOS ONE, 2015Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:Without quantum theory any understanding of molecular interactions is incomplete. In principal, chemistry, and even biology, can be fully derived from non-relativistic quantum mechanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantum methods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo hepatic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four compounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, Cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (over 5,000 people) safety profile warranting its exploitation as a new weapon for the current effort of malaria eradication. The results of our molecular modeling exceed current state-of-the-art computational methods. Drug discovery through quantum similarity is data-driven, agnostic to any particular target or disease process that can evaluate multiple phenotypic, target-specific, or co-crystal structural data. This allows the incorporation of additional pharmacological requirements, as well as rapid exploration of novel chemical spaces for therapeutic applications.
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Liver-stage Quantum Components.
2015Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:Quantum similarity of A. GNF-Pf-1498 and the quinoline-macrolide hybrid B. Cethromycin that is related to CHEMBL440116 as well as chemical structures of C. GNF-Pf-1498 and D. Cethromycin.
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in vitro inhibition of liver stage malaria.
2015Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:A. Three of the new compounds indicated 30%, 96% and 55% inhibition while Cethromycin alone at 20 μM had 54% inhibition. The individual components of Cethromycin-quinoline and erythromycin, were inactive. Error is average of duplicate wells performed in two independent biologic experiments with different preparations of sporozoites. B. Microscopic image taken at 20x magnification of near 95% inhibition by T5531873. 50,000 Hepa1-6 cells were seeded in each well 24 hrs prior to infection with ~60,000 P. berghei sporozoites. The 2E6 anti-HSP70 antibody was used for immunofluorescent numeration of infected cells.
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in vivo inhibition.
2015Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:10,000 sporozoites were inoculated by tailvein injection and mice were sacrificed 40 hours later, livers were harvested, placed in RNAzol and parasite levels determined by realtime PCR from cDNA from reverse transcription. Relative fluorescent units were compared to control to determine percent inhibition. Cethromycin CET was administered only once while the other drugs were given twice 24 hours apart from each dose. Two drugs related to CET, quinolone (QN) and erythromycin (ERY), had only marginal effect on parasite growth. CET’s effectiveness increased with dosage, reaching 60% reduction at 50 mg/kg. CET was also able to eliminate parasite infection when combined with low dose of PQ. All three novel compounds (T0507-9950, T5531873, T0510-7064) demonstrated significant inhibitory effect on parasite proliferation. Error is standard error of mean of three mice with real time PCR performed in duplicate for transcript levels in each mouse. B. Actual log values of relative fluorescent units from controls, Cethromycin 12 mg/kg, primaquine 15 mg/kg and in combination are depicted. The combination has a 4 fold drop in relative fluorescent units compared to primaquine.
David J. Sullivan - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity
2016Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:Without quantum theory any understanding of molecular interactions is incomplete. In prin-cipal, chemistry, and even biology, can be fully derived from non-relativistic quantum me-chanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantummethods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo he-patic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four com-pounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, Cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (ove
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Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity.
PLOS ONE, 2015Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:Without quantum theory any understanding of molecular interactions is incomplete. In principal, chemistry, and even biology, can be fully derived from non-relativistic quantum mechanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantum methods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo hepatic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four compounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, Cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (over 5,000 people) safety profile warranting its exploitation as a new weapon for the current effort of malaria eradication. The results of our molecular modeling exceed current state-of-the-art computational methods. Drug discovery through quantum similarity is data-driven, agnostic to any particular target or disease process that can evaluate multiple phenotypic, target-specific, or co-crystal structural data. This allows the incorporation of additional pharmacological requirements, as well as rapid exploration of novel chemical spaces for therapeutic applications.
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Liver-stage Quantum Components.
2015Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:Quantum similarity of A. GNF-Pf-1498 and the quinoline-macrolide hybrid B. Cethromycin that is related to CHEMBL440116 as well as chemical structures of C. GNF-Pf-1498 and D. Cethromycin.
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in vitro inhibition of liver stage malaria.
2015Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:A. Three of the new compounds indicated 30%, 96% and 55% inhibition while Cethromycin alone at 20 μM had 54% inhibition. The individual components of Cethromycin-quinoline and erythromycin, were inactive. Error is average of duplicate wells performed in two independent biologic experiments with different preparations of sporozoites. B. Microscopic image taken at 20x magnification of near 95% inhibition by T5531873. 50,000 Hepa1-6 cells were seeded in each well 24 hrs prior to infection with ~60,000 P. berghei sporozoites. The 2E6 anti-HSP70 antibody was used for immunofluorescent numeration of infected cells.
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in vivo inhibition.
2015Co-Authors: David J. Sullivan, Yi Liu, Bryan T. Mott, Nikola Kaludov, Martin N. MartinovAbstract:10,000 sporozoites were inoculated by tailvein injection and mice were sacrificed 40 hours later, livers were harvested, placed in RNAzol and parasite levels determined by realtime PCR from cDNA from reverse transcription. Relative fluorescent units were compared to control to determine percent inhibition. Cethromycin CET was administered only once while the other drugs were given twice 24 hours apart from each dose. Two drugs related to CET, quinolone (QN) and erythromycin (ERY), had only marginal effect on parasite growth. CET’s effectiveness increased with dosage, reaching 60% reduction at 50 mg/kg. CET was also able to eliminate parasite infection when combined with low dose of PQ. All three novel compounds (T0507-9950, T5531873, T0510-7064) demonstrated significant inhibitory effect on parasite proliferation. Error is standard error of mean of three mice with real time PCR performed in duplicate for transcript levels in each mouse. B. Actual log values of relative fluorescent units from controls, Cethromycin 12 mg/kg, primaquine 15 mg/kg and in combination are depicted. The combination has a 4 fold drop in relative fluorescent units compared to primaquine.
Angela M. Nilius - One of the best experts on this subject based on the ideXlab platform.
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ribosome affinity and the prolonged molecular postantibiotic effect of Cethromycin abt 773 in haemophilus influenzae
International Journal of Antimicrobial Agents, 2004Co-Authors: Ping Zhong, Phil Merta, Xiaoan Ruan, John O Capobianco, Robert K Flamm, Angela M. NiliusAbstract:Cethromycin (ABT-773) is a new ketolide currently in clinical trials, for treatment of community acquired respiratory tract infections. The drug is active in vitro and in vivo against Haemophilus influenzae. In this study, the mechanism of action of Cethromycin was investigated in H. influenzae. The drug effect was studied using in vitro transcription-translation and whole cell amino acid incorporation. Both Cethromycin and erythromycin inhibit protein synthesis with similar potencies; Cethromycin, however, had a prolonged molecular postantibiotic effect (PAE) compared with erythromycin which was consistent with previously reported microbiological data. Ribosome binding assay using ribosomes isolated from H. influenzae NP200 revealed that the ribosome binding affinity of Cethromycin was more than 20-fold tighter than that of erythromycin. Studies of binding kinetics showed that the tight binding of Cethromycin mainly contributed to the 20-fold slower dissociation from cells. Further studies showed Cethromycin had a four-fold faster drug accumulation rate than erythromycin. Therefore, the tight binding of Cethromycin with ribosomes likely contributed to the faster drug accumulation, slower dissociation from cells and prolonged molecular PAE of Cethromycin for H. influenzae.
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Ketolides: the future of the macrolides?
Current Opinion in Pharmacology, 2002Co-Authors: Angela M. NiliusAbstract:The prevalence of antibiotic resistance in bacterial pathogens associated with community-acquired respiratory tract infections is increasing. Ketolides, semi-synthetic derivatives of erythromycin, overcome the macrolide resistance mechanisms found in Streptococcus pneumoniae and Streptococcus pyogenes, two key pathogens. They also have improved potency and longer post-antibiotic effects, while maintaining the antibacterial spectrum of the macrolide class. The new ketolides Cethromycin (ABT-773) and telithromycin have overall antibacterial properties that suggest they will be clinically useful new antibiotics and are undergoing clinical development and regulatory review.
Ralf René Reinert - One of the best experts on this subject based on the ideXlab platform.
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tract infections
2014Co-Authors: Ralf René ReinertAbstract:Ketolides are a new class of semi-synthetic agents derived from erythromycin A designed to overcome erythromycin A resistance in Streptococcus pneumoniae. Telithromycin (HMR 3647) is the first member of this new class to be approved for clinical use. Cethromycin (ABT-773) has been developed up to Phase III, but its further development seems questionable at the moment. Other ketolides are only in the first stages of preclinical development and may not be available within the foreseeable future. Ketolide compounds inhibit bacterial protein synthesis by interacting with the peptidyl transferase site of the 50S ribosomal subunit, and interact closely with domains II at A752 and V at A2058 and A2059 of the 23S rRNA. These compounds also inhibit the formation of the 50S subunit of the ribosome. Ketolides show good activity against the Gram-positive bacteria responsible for respiratory tract infections including penicillin G- and erythromycin A-resistant S. pneumoniae. The 15 clinical trials with telithromycin published to date include four randomized, double-blind comparative trials and three open-label studies in community-acquired pneumonia, three randomized double-blind trials in acute exacerbation of chronic bronchitis, two randomized double-blind trials in pharyngitis, and two double-blind comparative trials and one open-label trial in acute maxillary sinusitis. Clinical response rates were favourable in all clinical trials, with eradication rates in patients with pneumococcal bacteraemia and penicillin G- and erythromycin A-resistant pneumococcal infections a
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Clinical efficacy of ketolides in the treatment of respiratory tract infections
Journal of Antimicrobial Chemotherapy, 2004Co-Authors: Ralf René ReinertAbstract:Ketolides are a new class of semi-synthetic agents derived from erythromycin A designed to overcome erythromycin A resistance in Streptococcus pneumoniae. Telithromycin (HMR 3647) is the first member of this new class to be approved for clinical use. Cethromycin (ABT-773) has been developed up to Phase III, but its further development seems questionable at the moment. Other ketolides are only in the first stages of preclinical development and may not be available within the foreseeable future. Ketolide compounds inhibit bacterial protein synthesis by interacting with the peptidyl transferase site of the 50S ribosomal subunit, and interact closely with domains II at A752 and V at A2058 and A2059 of the 23S rRNA. These compounds also inhibit the formation of the 50S subunit of the ribosome. Ketolides show good activity against the Gram- positive bacteria responsible for respiratory tract infections including penicillin G- and erythromycin A-resistant S. pneumoniae. The 15 clinical trials with telithromycin published to date include four randomized, double-blind comparative trials and three open-label studies in community-acquired pneumonia, three randomized double-blind trials in acute exacerbation of chronic bronchitis, two randomized double-blind trials in pharyngitis, and two double-blind comparative trials and one open-label trial in acute maxillary sinusitis. Clinical response rates were favourable in all clinical trials, with eradication rates in patients with pneumococcal bacteraemia and penicillin G- and erythromycin A-resistant pneumococcal infections at least as high as those of comparators. As resistance to macrolides continues to emerge, the availability of other ketolides besides telithromycin and a development programme for the application of ketolides in children would appear to be warranted to obtain a new class of antibiotics that may one day replace macro- lides.
Max Maurin - One of the best experts on this subject based on the ideXlab platform.
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New therapeutic approaches for treatment of tularaemia: a review
Frontiers in Cellular and Infection Microbiology, 2014Co-Authors: Sandrine Boisset, Yvan Caspar, Vivien Sutera, Max MaurinAbstract:Antibiotic treatment of tularaemia is based on a few drugs, including the fluoroquinolones, the tetracyclines and the aminoglycosides. Because no effective and safe vaccine is currently available, tularaemia prophylaxis following proven exposure to F. tularensis also relies on administration of antibiotics. A number of reasons make it necessary to search for new therapeutic alternatives: the potential toxicity of first-line drugs, especially in children and pregnant women; a high rate of treatment relapses and failures, especially for severe and/or suppurated forms of the disease; and the possible use of antibiotic-resistant strains in the context of a biological threat. This review presents novel therapeutic approaches that have been explored in recent years to improve tularaemia patients’ management and prognosis. First, the activities of newly available antibiotic compounds were evaluated against F. tularensis, including tigecycline (a glycylcycline), ketolides (telithromycin and Cethromycin) and fluoroquinolones (moxifloxacin, gatifloxacin, trovafloxacin and grepafloxacin). The liposome delivery of some antibiotics was evaluated. The effect of antimicrobial peptides against F. tularensis was also considered. Other drugs were evaluated for their ability to suppress the intracellular multiplication of F. tularensis. The effects of the modulation of the innate immune response (especially via TLR receptors) on the course of F. tularensis infection were characterized. Another approach was the administration of specific antibodies to induce passive resistance to F. tularensis infection. All of these studies highlight the need to develop new therapeutic strategies to improve the management of patients with tularaemia. Many possibilities exist, some unexplored. Moreover, it is likely that new therapeutic alternatives that are effective against this intracellular pathogen could be, at least partially, extrapolated to other human pathogens.
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New therapeutic approaches for treatment of tularaemia: a review.
Frontiers in Cellular and Infection Microbiology, 2014Co-Authors: Sandrine Boisset, Yvan Caspar, Vivien Sutera, Max MaurinAbstract:: Antibiotic treatment of tularaemia is based on a few drugs, including the fluoroquinolones (e.g., ciprofloxacin), the tetracyclines (e.g., doxycycline), and the aminoglycosides (streptomycin and gentamicin). Because no effective and safe vaccine is currently available, tularaemia prophylaxis following proven exposure to F. tularensis also relies on administration of antibiotics. A number of reasons make it necessary to search for new therapeutic alternatives: the potential toxicity of first-line drugs, especially in children and pregnant women; a high rate of treatment relapses and failures, especially for severe and/or suppurated forms of the disease; and the possible use of antibiotic-resistant strains in the context of a biological threat. This review presents novel therapeutic approaches that have been explored in recent years to improve tularaemia patients' management and prognosis. These new strategies have been evaluated in vitro, in axenic media and cell culture systems and/or in animal models. First, the activities of newly available antibiotic compounds were evaluated against F. tularensis, including tigecycline (a glycylcycline), ketolides (telithromycin and Cethromycin), and fluoroquinolones (moxifloxacin, gatifloxacin, trovafloxacin and grepafloxacin). The liposome delivery of some antibiotics was evaluated. The effect of antimicrobial peptides against F. tularensis was also considered. Other drugs were evaluated for their ability to suppress the intracellular multiplication of F. tularensis. The effects of the modulation of the innate immune response (especially via TLR receptors) on the course of F. tularensis infection was characterized. Another approach was the administration of specific antibodies to induce passive resistance to F. tularensis infection. All of these studies highlight the need to develop new therapeutic strategies to improve the management of patients with tularaemia. Many possibilities exist, some unexplored. Moreover, it is likely that new therapeutic alternatives that are effective against this intracellular pathogen could be, at least partially, extrapolated to other human pathogens.