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In JoVE (1)
- A Robust Pneumonia Model in Immunocompetent Rodents to Evaluate Antibacterial Efficacy against S. pneumoniae, H. influenzae, K. pneumoniae, P. aeruginosa or A. baumannii
Other Publications (3)
Articles by Jennifer L. Hoover in JoVE
A Robust Pneumonia Model in Immunocompetent Rodents to Evaluate Antibacterial Efficacy against S. pneumoniae, H. influenzae, K. pneumoniae, P. aeruginosa or A. baumannii
Jennifer L. Hoover1, Thomas F. Lewandowski1, Cindy L. Mininger1, Christine M. Singley1, Scott Sucoloski1, Stephen Rittenhouse1
1Antibacterial Discovery Performance Unit, GlaxoSmithKline
Other articles by Jennifer L. Hoover on PubMed
Novel Hydroxyl Tricyclics (e.g., GSK966587) As Potent Inhibitors of Bacterial Type IIA Topoisomerases
Bioorganic & Medicinal Chemistry Letters. Oct, 2013 | Pubmed ID: 23968823
During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.
Bioorganic & Medicinal Chemistry Letters. May, 2016 | Pubmed ID: 27055939
During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin Against Gram-Positive Organisms Using Data From Murine Infection Models
Antimicrobial Agents and Chemotherapy. Nov, 2016 | Pubmed ID: 27872075
Gepotidacin (formerly GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with in vitro activity against conventional and biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae Using neutropenic murine thigh- and lung-infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. pneumoniae were characterized. Single dose PK data from uninfected mice (16-128 mg/kg SC) were fit with candidate models. Dose-fractionation studies (one isolate/organism; 2-512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2-2048 mg/kg/day; MIC ranges: S. aureus 0.5-2 mg/L; S. pneumoniae: 0.125-1 mg/L) were conducted. In vivo post-antibiotic effects (PAE) were also evaluated. Relationships between change from baseline in log10 CFU at 24 h and free-drug plasma AUC:MIC ratio, Cmax:MIC ratio, and %T>MIC were evaluated using Hill-type models. Plasma and ELF PK data were best fit by a 4-compartment model with linear distributional clearances, a capacity-limited clearance, and a first-order absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the growth of both organisms was poor in the murine lung-infection model, lung efficacy data were not reported. As determined using the murine thigh-infection model, free-drug plasma AUC:MIC ratio was the PK-PD index most closely associated with efficacy (r(2)=0.936 and 0.897 for S. aureus and S. pneumoniae, respectively). Median free-drug plasma AUC:MIC ratios of 13.4 and 58.9 for S. aureus, and 7.86 and 16.9 for S. pneumoniae, were associated with net bacterial stasis and a 1-log10 CFU reduction from baseline, respectively. Dose-independent PAEs of 3.07-12.5h and 5.25-8.46h were demonstrated for S. aureus and S. pneumoniae, respectively.