11 results on '"Aubart K"'
Search Results
2. Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection.
- Author
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Hoover J, Lewandowski T, Straub RJ, Novick SJ, DeMarsh P, Aubart K, Rittenhouse S, and Zalacain M
- Subjects
- Amidohydrolases antagonists & inhibitors, Amidohydrolases metabolism, Animals, Anti-Bacterial Agents blood, Anti-Bacterial Agents pharmacology, Area Under Curve, Bacterial Proteins antagonists & inhibitors, Bacterial Proteins metabolism, Bridged Bicyclo Compounds, Heterocyclic blood, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Enzyme Inhibitors blood, Enzyme Inhibitors pharmacology, Haemophilus Infections blood, Haemophilus Infections microbiology, Haemophilus influenzae drug effects, Haemophilus influenzae enzymology, Haemophilus influenzae growth & development, Hydroxamic Acids blood, Hydroxamic Acids pharmacology, Lung drug effects, Lung microbiology, Male, Mice, Microbial Sensitivity Tests, Pneumonia, Pneumococcal blood, Pneumonia, Pneumococcal microbiology, Rats, Rats, Sprague-Dawley, Staphylococcal Infections blood, Staphylococcal Infections microbiology, Staphylococcus aureus drug effects, Staphylococcus aureus enzymology, Staphylococcus aureus growth & development, Streptococcus pneumoniae drug effects, Streptococcus pneumoniae enzymology, Streptococcus pneumoniae growth & development, Anti-Bacterial Agents pharmacokinetics, Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics, Enzyme Inhibitors pharmacokinetics, Haemophilus Infections drug therapy, Hydroxamic Acids pharmacokinetics, Pneumonia, Pneumococcal drug therapy, Staphylococcal Infections drug therapy
- Abstract
GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitro activity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivo pharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniae and Haemophilus influenzae (mouse lung model) and with Staphylococcus aureus (rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependent in vivo efficacy against multiple isolates of S. pneumoniae, H. influenzae, and S. aureus. Dose fractionation studies with two S. pneumoniae and S. aureus isolates showed that therapeutic outcome correlated best with the free AUC/MIC (fAUC/MIC) index in S. pneumoniae (R(2), 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus (R(2), 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis and for a 1-log10 reduction in bacterial burden were 8.1 and 14.4 for 11 S. pneumoniae isolates (R(2), 0.62) and 7.2 and 13.0 for five H. influenzae isolates (R(2), 0.93). The data showed that for eight S. aureus isolates, fAUC correlated better with efficacy than fAUC/MIC (R(2), 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 4 μg/ml). Median fAUCs of 2.1 and 6.3 μg · h/ml were associated with stasis and 1-log10 reductions, respectively, for S. aureus., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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3. Frequency of Spontaneous Resistance to Peptide Deformylase Inhibitor GSK1322322 in Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae.
- Author
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Min S, Ingraham K, Huang J, McCloskey L, Rilling S, Windau A, Pizzollo J, Butler D, Aubart K, Miller LA, Zalacain M, Holmes DJ, and O'Dwyer K
- Subjects
- Haemophilus Infections drug therapy, Humans, Microbial Sensitivity Tests methods, Pneumococcal Infections drug therapy, Staphylococcal Infections drug therapy, Amidohydrolases antagonists & inhibitors, Anti-Bacterial Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Haemophilus influenzae drug effects, Hydroxamic Acids pharmacology, Staphylococcus aureus drug effects, Streptococcus pneumoniae drug effects, Streptococcus pyogenes drug effects
- Abstract
The continuous emergence of multidrug-resistant pathogenic bacteria is compromising the successful treatment of serious microbial infections. GSK1322322, a novel peptide deformylase (PDF) inhibitor, shows good in vitro antibacterial activity and has demonstrated safety and efficacy in human proof-of-concept clinical studies. In vitro studies were performed to determine the frequency of resistance (FoR) to this antimicrobial agent in major pathogens that cause respiratory tract and skin infections. Resistance to GSK1322322 occurred at high frequency through loss-of-function mutations in the formyl-methionyl transferase (FMT) protein in Staphylococcus aureus (4/4 strains) and Streptococcus pyogenes (4/4 strains) and via missense mutations in Streptococcus pneumoniae (6/21 strains), but the mutations were associated with severe in vitro and/or in vivo fitness costs. The overall FoR to GSK1322322 was very low in Haemophilus influenzae, with only one PDF mutant being identified in one of four strains. No target-based mutants were identified from S. pyogenes, and only one or no PDF mutants were isolated in three of the four S. aureus strains studied. In S. pneumoniae, PDF mutants were isolated from only six of 21 strains tested; an additional 10 strains did not yield colonies on GSK1322322-containing plates. Most of the PDF mutants characterized from those three organisms (35/37 mutants) carried mutations in residues at or in close proximity to one of three highly conserved motifs that are part of the active site of the PDF protein, with 30 of the 35 mutations occurring at position V71 (using the S. pneumoniae numbering system)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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- View/download PDF
4. Microbiome changes in healthy volunteers treated with GSK1322322, a novel antibiotic targeting bacterial peptide deformylase.
- Author
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Arat S, Spivak A, Van Horn S, Thomas E, Traini C, Sathe G, Livi GP, Ingraham K, Jones L, Aubart K, Holmes DJ, Naderer O, and Brown JR
- Subjects
- Betaproteobacteria drug effects, Betaproteobacteria genetics, Bifidobacterium drug effects, Bifidobacterium genetics, Double-Blind Method, Gammaproteobacteria drug effects, Gammaproteobacteria genetics, Healthy Volunteers, High-Throughput Nucleotide Sequencing, Humans, RNA, Ribosomal, 16S genetics, Amidohydrolases antagonists & inhibitors, Anti-Bacterial Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Hydroxamic Acids pharmacology, Microbiota drug effects, Microbiota genetics
- Abstract
GSK1322322 is a novel antibacterial agent under development, and it has known antibacterial activities against multidrug-resistant respiratory and skin pathogens through its inhibition of the bacterial peptide deformylase. Here, we used next-generation sequencing (NGS) of the bacterial 16S rRNA genes from stool samples collected from 61 healthy volunteers at the predosing and end-of-study time points to determine the effects of GSK1322322 on the gastrointestinal (GI) microbiota in a phase I, randomized, double-blind, and placebo-controlled study. GSK1322322 was administered either intravenously (i.v.) only or in an oral-i.v. combination in single- and repeat-dose-escalation infusions. Analysis of the 16S rRNA sequence data found no significant changes in the relative abundances of GI operational taxonomic units (OTUs) between the prestudy and end-of-study samples for either the placebo- or i.v.-only-treated subjects. However, oral-i.v. treatment resulted in significant decreases in some bacterial taxa, the Firmicutes and Bacteroidales, and increases in others, the Betaproteobacteria, Gammaproteobacteria, and Bifidobacteriaceae. Microbiome diversity plots clearly differentiated the end-of-study oral-i.v.-dosed samples from all others collected. The changes in genome function as inferred from species composition suggest an increase in bacterial transporter and xenobiotic metabolism pathways in these samples. A phylogenetic analysis of the peptide deformylase protein sequences collected from the published genomes of clinical isolates previously tested for GSK1322322 in vitro susceptibility and GI bacterial reference genomes suggests that antibiotic target homology is one of several factors that influences the response of GI microbiota to this antibiotic. Our study shows that dosing regimen and target class are important factors when considering the impact of antibiotic usage on GI microbiota. (This clinical trial was registered at the GlaxoSmithKline Clinical Study Register under study identifier PDF 113376.)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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5. In vitro and intracellular activities of peptide deformylase inhibitor GSK1322322 against Legionella pneumophila isolates.
- Author
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Dubois J, Dubois M, Martel JF, Aubart K, and Butler D
- Subjects
- Anti-Bacterial Agents therapeutic use, Azithromycin pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Humans, Hydroxamic Acids therapeutic use, Legionnaires' Disease drug therapy, Levofloxacin pharmacology, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Hydroxamic Acids pharmacology, Legionella pneumophila drug effects
- Abstract
GSK1322322, a novel peptide deformylase inhibitor currently in development as an oral and intravenous agent for the treatment of hospitalized community-acquired bacterial pneumonia, showed poor in vitro activity against a panel of 50 Legionella pneumophila strains, with MICs ranging from 1 to 16 μg/ml and an MIC90 of 16 μg/ml, but very potent intracellular activity, with the minimum extracellular concentrations capable of inhibiting intracellular proliferation (MIECs) ranging from 0.12 to 2 μg/ml and 98% of the strains being inhibited by concentrations of ≤ 1 μg/ml., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
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6. Potent sub-MIC effect of GSK1322322 and other peptide deformylase inhibitors on in vitro growth of Staphylococcus aureus.
- Author
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Butler D, Chen D, O'Dwyer K, Lewandowski T, Aubart K, and Zalacain M
- Subjects
- Methicillin-Resistant Staphylococcus aureus drug effects, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Enzyme Inhibitors pharmacology, Hydroxamic Acids pharmacology, Staphylococcus aureus drug effects
- Abstract
Peptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). GSK1322322 is a novel PDF inhibitor that is in phase II clinical development for the treatment of lower respiratory tract and skin infections. We have discovered that PDF inhibitors can prevent S. aureus in vitro growth for up to 6 h at concentrations 8- to 32-fold below their MICs. This phenomenon seems specific to PDF inhibitors, as none of the antimicrobial agents with alternative mechanisms of action tested show such a potent and widespread effect. It also appears limited to S. aureus, as PDF inhibitors do not show such an inhibition of growth at sub-MIC levels in Streptococcus pneumoniae or Haemophilus influenzae. Analysis of the effect of GSK1322322 on the early growth of 100 randomly selected S. aureus strains showed that concentrations equal to or below 1/8× MIC inhibited growth of 91% of the strains tested for 6 h, while the corresponding amount of moxifloxacin or linezolid only affected the growth of 1% and 6% of strains, respectively. Furthermore, the sub-MIC effect demonstrated by GSK1322322 appears more substantial on those strains at the higher end of the MIC spectrum. These effects may impact the clinical efficacy of GSK1322322 in serious infections caused by multidrug-resistant S. aureus.
- Published
- 2014
- Full Text
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7. Staphylococcus aureus formyl-methionyl transferase mutants demonstrate reduced virulence factor production and pathogenicity.
- Author
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Lewandowski T, Huang J, Fan F, Rogers S, Gentry D, Holland R, Demarsh P, Aubart K, and Zalacain M
- Subjects
- Amidohydrolases antagonists & inhibitors, Animals, Anti-Bacterial Agents pharmacology, Bacterial Toxins biosynthesis, Bacterial Toxins genetics, Exotoxins biosynthesis, Exotoxins genetics, Hemolysin Proteins biosynthesis, Hemolysin Proteins genetics, Leukocidins biosynthesis, Leukocidins genetics, Male, Mice, Mice, Inbred CBA, Microbial Sensitivity Tests, Pyelonephritis microbiology, Staphylococcal Infections, Staphylococcus aureus pathogenicity, Virulence Factors, Drug Resistance, Bacterial genetics, Hydroxymethyl and Formyl Transferases genetics, Staphylococcus aureus enzymology, Staphylococcus aureus genetics
- Abstract
Inhibitors of peptide deformylase (PDF) represent a new class of antibacterial agents with a novel mechanism of action. Mutations that inactivate formyl methionyl transferase (FMT), the enzyme that formylates initiator methionyl-tRNA, lead to an alternative initiation of protein synthesis that does not require deformylation and are the predominant cause of resistance to PDF inhibitors in Staphylococcus aureus. Here, we report that loss-of-function mutations in FMT impart pleiotropic effects that include a reduced growth rate, a nonhemolytic phenotype, and a drastic reduction in production of multiple extracellular proteins, including key virulence factors, such as α-hemolysin and Panton-Valentine leukocidin (PVL), that have been associated with S. aureus pathogenicity. Consequently, S. aureus FMT mutants are greatly attenuated in neutropenic and nonneutropenic murine pyelonephritis infection models and show very high survival rates compared with wild-type S. aureus. These newly discovered effects on extracellular virulence factor production demonstrate that FMT-null mutants have a more severe fitness cost than previously anticipated, leading to a substantial loss of pathogenicity and a restricted ability to produce an invasive infection.
- Published
- 2013
- Full Text
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8. Comparative analysis of the antibacterial activity of a novel peptide deformylase inhibitor, GSK1322322.
- Author
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O'Dwyer K, Hackel M, Hightower S, Hoban D, Bouchillon S, Qin D, Aubart K, Zalacain M, and Butler D
- Subjects
- Amidohydrolases antagonists & inhibitors, Amidohydrolases metabolism, Bacterial Proteins antagonists & inhibitors, Bacterial Proteins metabolism, Clinical Trials as Topic, Drug Resistance, Multiple, Bacterial drug effects, Haemophilus influenzae enzymology, Haemophilus influenzae growth & development, Microbial Sensitivity Tests, Moraxella catarrhalis enzymology, Moraxella catarrhalis growth & development, Staphylococcus aureus enzymology, Staphylococcus aureus growth & development, Streptococcus pneumoniae enzymology, Streptococcus pneumoniae growth & development, Streptococcus pyogenes enzymology, Streptococcus pyogenes growth & development, beta-Lactamases metabolism, Anti-Bacterial Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Enzyme Inhibitors pharmacology, Haemophilus influenzae drug effects, Hydroxamic Acids pharmacology, Moraxella catarrhalis drug effects, Staphylococcus aureus drug effects, Streptococcus pneumoniae drug effects, Streptococcus pyogenes drug effects
- Abstract
GSK1322322 is a novel peptide deformylase (PDF) inhibitor being developed for the intravenous and oral treatment of acute bacterial skin and skin structure infections and hospitalized patients with community-acquired pneumonia. The activity of GSK1322322 was tested against a global collection of clinical isolates of Haemophilus influenzae (n = 2,370), Moraxella catarrhalis (n = 115), Streptococcus pneumoniae (n = 947), Streptococcus pyogenes (n = 617), and Staphylococcus aureus (n = 940), including strains resistant to one or more marketed antibiotics. GSK1322322 had an MIC(90) of 1 μg/ml against M. catarrhalis and 4 μg/ml against H. influenzae, with 88.8% of β-lactamase-positive strains showing growth inhibition at that concentration. All S. pneumoniae strains were inhibited by ≤ 4 μg/ml of GSK1322322, with an MIC(90) of 2 μg/ml. Pre-existing resistance mechanisms did not affect its potency, as evidenced by the MIC(90) of 1 μg/ml for penicillin, levofloxacin, and macrolide-resistant S. pneumoniae. GSK1322322 was very potent against S. pyogenes strains, with an MIC(90) of 0.5 μg/ml, irrespective of their macrolide resistance phenotype. This PDF inhibitor was also active against S. aureus strains regardless of their susceptibility to methicillin, macrolides, or levofloxacin, with an MIC(90) of 4 μg/ml in all cases. Time-kill studies showed that GSK1322322 had bactericidal activity against S. pneumoniae, H. influenzae, S. pyogenes, and S. aureus, demonstrating a ≥ 3-log(10) decrease in the number of CFU/ml at 4× MIC within 24 h in 29 of the 33 strains tested. Given the antibacterial potency demonstrated against this panel of organisms, GSK1322322 represents a valuable alternative therapy for the treatment of infectious diseases caused by drug-resistant pathogens.
- Published
- 2013
- Full Text
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9. Design, synthesis and antibacterial activity of 3-methylenepyrrolidine formyl hydroxyamino derivatives as novel peptide deformylase inhibitors.
- Author
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Shi W, Ma H, Duan Y, Aubart K, Fang Y, Zonis R, Yang L, and Hu W
- Subjects
- Amidohydrolases metabolism, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Drug Design, Drug Resistance, Bacterial drug effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Haemophilus influenzae drug effects, Methicillin-Resistant Staphylococcus aureus drug effects, Microbial Sensitivity Tests, Pyrrolidines chemical synthesis, Pyrrolidines pharmacology, Amidohydrolases antagonists & inhibitors, Anti-Bacterial Agents chemical synthesis, Enzyme Inhibitors chemical synthesis, Pyrrolidines chemistry
- Abstract
The synthesis and antibacterial activity of 3-methylenepyrrolidine formyl hydroxyamino derivatives are reported. The antibacterial activities of these derivatives were evaluated to discover SAR at P(1') and P(3') positions, and most of these derivatives exhibit better in vitro antibacterial activity than existing drugs against drug-resistant clinical isolates including MRSA, PRSP, and Haemophilus influenzae., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
10. Peptide deformylase inhibitors.
- Author
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Aubart K and Zalacain M
- Subjects
- Amidohydrolases chemistry, Animals, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Drug Design, Humans, Structure-Activity Relationship, Amidohydrolases antagonists & inhibitors, Amidohydrolases metabolism, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology
- Published
- 2006
- Full Text
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11. Structural variation and inhibitor binding in polypeptide deformylase from four different bacterial species.
- Author
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Smith KJ, Petit CM, Aubart K, Smyth M, McManus E, Jones J, Fosberry A, Lewis C, Lonetto M, and Christensen SB
- Subjects
- Amino Acid Sequence, Aminopeptidases metabolism, Bacterial Proteins antagonists & inhibitors, Binding Sites, Crystallography, X-Ray, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Escherichia coli drug effects, Escherichia coli enzymology, Haemophilus influenzae drug effects, Haemophilus influenzae enzymology, Kinetics, Microbial Sensitivity Tests, Models, Molecular, Molecular Sequence Data, Peptides, Protein Binding, Protein Conformation, Sequence Homology, Amino Acid, Staphylococcus aureus drug effects, Staphylococcus aureus enzymology, Streptococcus pneumoniae drug effects, Streptococcus pneumoniae enzymology, Amidohydrolases, Aminopeptidases antagonists & inhibitors, Aminopeptidases chemistry, Bacterial Proteins chemistry, Bacterial Proteins metabolism, Enzyme Inhibitors metabolism
- Abstract
Polypeptide deformylase (PDF) catalyzes the deformylation of polypeptide chains in bacteria. It is essential for bacterial cell viability and is a potential antibacterial drug target. Here, we report the crystal structures of polypeptide deformylase from four different species of bacteria: Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli. Comparison of these four structures reveals significant overall differences between the two Gram-negative species (E. coli and H. influenzae) and the two Gram-positive species (S. pneumoniae and S. aureus). Despite these differences and low overall sequence identity, the S1' pocket of PDF is well conserved among the four enzymes studied. We also describe the binding of nonpeptidic inhibitor molecules SB-485345, SB-543668, and SB-505684 to both S. pneumoniae and E. coli PDF. Comparison of these structures shows similar binding interactions with both Gram-negative and Gram-positive species. Understanding the similarities and subtle differences in active site structure between species will help to design broad-spectrum polypeptide deformylase inhibitor molecules.
- Published
- 2003
- Full Text
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