Comparative Analysis of the Antibacterial Activity of a Novel Peptide Deformylase Inhibitor, GSK1322322

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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 dosedependent 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 (fC max )/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-log 10 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 g/ml). Median fAUCs of 2.1 and 6.3 g · h/ml were associated with stasis and 1-log 10 reductions, respectively, for S. aureus.

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confidence: 99%

Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection

Hoover

Lewandowski

Straub

et al. 2016

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“…A large number of structurally diverse PDF inhibitors have been identified over the years, including several compounds with demonstrated in vivo efficacy and good safety profiles (4), some of which have progressed to clinical trials (5,6). GSK1322322 is a novel nonpeptidic PDF inhibitor from the hydrazide class that shows good in vitro antibacterial activity (7) and has demonstrated safety and efficacy in human proof-of-concept clinical studies (8)(9)(10)(11).…”

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confidence: 99%

Frequency of Spontaneous Resistance to Peptide Deformylase Inhibitor GSK1322322 in Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae

Min

Ingraham

Huang

et al. 2015

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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).

“…The 1,500-mg b.i.d. dose of GSK1322322 was chosen on the basis of the following results: demonstrated safety of a powder-in-bottle formulation of GSK1322322 in healthy volunteers (12,14), in vitro activity against Streptococcus pyogenes (10); in vivo efficacy against multiple drug-resistant strains of S. aureus in a rat subcutaneous abscess infection model (8), and Monte Carlo simulations performed at the 1,500-mg dose level with 10,000 subjects to simulate a 24-h area under the concentration-time curve (AUC 0-24 ) of 92.5 g·h/ml (62.2 to 137 g·h/ml), which is greater than the AUC that resulted in a 3.4-to 5.3-log 10 CFU/abscess reduction compared with a vehicle-treated control group (extrapolated AUC 0-24 , 54.6 to 80.4 g·h/ml; data on file). The trial consisted of a screening visit (day 1), a 10-day treatment period (with assessments on days 2, 3, 4, 8, and 11), and follow-up evaluations 7 (days 16 to 19) and 28 (days 37 to 40) days after the last treatment dose.…”

Section: Methodsmentioning

confidence: 99%

“…Because of its unique mechanism of action, GSK1322322 shows no cross-resistance with currently approved antibacterial agents and is active against pathogens resistant to multiple classes of antibiotics, including MRSA, multidrug-resistant Streptococcus pneumoniae, and atypical pathogens, as demonstrated in vitro (9,10) and in murine models, including SSSIs (8,11).…”

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confidence: 99%

Safety, Tolerability, and Efficacy of GSK1322322 in the Treatment of Acute Bacterial Skin and Skin Structure Infections

Corey

Naderer

O’Riordan

et al. 2014

GSK1322322 represents a new class of antibiotics that targets an essential bacterial enzyme required for protein maturation, peptide deformylase. This multicenter, randomized, phase IIa study compared the safety, tolerability, and efficacy of GSK1322322 at 1,500 mg twice daily (b.i.d.) with that of linezolid at 600 mg b.i.d. in patients suspected of having Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). The primary endpoint was assessment of the safety of GSK1322322, and a key secondary endpoint was the number of subjects with a >20% decrease in lesion area from the baseline at 48 and 72 h after treatment initiation. GSK1322322 administration was associated with mild-to-moderate drug-related adverse events, most commonly, nausea, vomiting, diarrhea, and headache. Adverse events (86% versus 74%) and withdrawals (28% versus 11%) were more frequent in the GSK1322322-treated group. Treatment with GSK1322322 and linezolid was associated with >20% decreases from the baseline in the lesion area in 73% (36/49) and 92% (24/26) of the patients, respectively, at the 48-h assessment and in 96% (44/46) and 100% (25/25) of the patients, respectively, at the 72-h assessment. Reductions in exudate/pus, pain, and skin infection scores were comparable between the GSK1322322 and linezolid treatments. The clinical success rates within the intent-to-treat population and the per-protocol population that completed this study were 67 and 91%, respectively, in the GSK1322322-treated group and 89 and 100%, respectively, in the linezolid-treated group. These results will be used to guide dose selection in future studies with GSK1322322 to optimize its tolerability and efficacy in patients with ABSSSIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01209078 and at http://www.gsk-clinicalstudyregister.com [PDF113414].)