Efficacy of Human Exposures of Gepotidacin (GSK2140944) against Escherichia coli in a Rat Pyelonephritis Model.

Gepotidacin is a first-in-class triazaacenaphthylene antibacterial that inhibits bacterial type II topoisomerases and has in vitro activity against a range of bacterial pathogens, including Escherichia coli Urinary tract infections often progress to pyelonephritis and are a worldwide problem due to the prevalence of multidrug-resistant E. coli strains. This study evaluated the in vivo efficacy of gepotidacin against four strains of multidrug-resistant E. coli in a rat pyelonephritis model. Infected rats received controlled intravenous infusions of gepotidacin every 12 h for 4 days that recreated human systemic exposures from oral gepotidacin (800 or 1,500 mg twice daily for 4 days). Liquid chromatography-tandem mass spectrometry analysis of blood samples and kidney homogenates showed that gepotidacin levels were 6- to 7-fold higher in kidneys than in blood. Across experiments with 4-day gepotidacin treatments, bacterial CFU in kidneys were reduced by 2.9 to 4.9 log10 compared to pretreatment levels, and bladder CFU were reduced to the lower limit of detection (1.2 log10). The efficacies of 800- and 1,500-mg gepotidacin exposures were statistically similar. A time-course experiment indicated that a period of more than 24 h of gepotidacin treatment was required for efficacy and that 4 days were needed for maximal response. Overall, these results demonstrate that the recreated human exposures of gepotidacin studied were effective in an animal model of pyelonephritis caused by multidrug-resistant E. coli and that further evaluation for clinical use is warranted.

Reducing Antibacterial Development Risk for GSK1322322 by Exploring Potential Human Dose Regimens in Nonclinical Efficacy Studies Using Immunocompetent Rats.

Directly testing proposed clinical dosing regimens in nonclinical studies can reduce the risk during the development of novel antibacterial agents. Optimal dosing regimens can be identified in animal models by testing recreated human pharmacokinetic profiles. An example of this approach using continuous intravenous infusions of GSK1322322 in immunocompetent rats to evaluate recreated human exposures from phase I trials in pneumonia models with Streptococcus pneumoniae and Haemophilus influenzae and an abscess model with Staphylococcus aureus is presented. GSK1322322 was administered via continuous intravenous infusion to recreate 1,000- or 1,500-mg oral doses every 12 h in humans. Significant reductions (P ≤ 0.05 for all comparisons) in bacterial numbers compared with those for the baseline controls were observed for S. pneumoniae and H. influenzae (mean log10 reductions, 1.6 to ≥2.7 and 1.8 to 3.3 CFU/lungs, respectively) with the recreated 1,000-mg oral dose. This profile was also efficacious against S. aureus (mean log10 reduction, 1.9 to 2.4 CFU/abscess). There was a nonsignificant trend for improved efficacy against S. aureus with the 1,500-mg oral dose (mean log10 reduction, 2.4 to 3.1 CFU/abscess). These results demonstrate that the human oral 1,000- or 1,500-mg exposure profiles of GSK1322322 recreated in rats were effective against representative community-associated pathogens and supported selection of the 1,500-mg oral dose given every 12 h for a phase II clinical skin infection study. Furthermore, this work exemplifies how the testing of recreated human pharmacokinetic profiles can be incorporated into the development process and serve as an aid for selecting optimal dosing regimens prior to conducting large-scale clinical studies.

Challenges of antibacterial discovery revisited.

The discovery of novel antibiotic classes has not kept pace with the growing threat of bacterial resistance. Antibiotic candidates that act at new targets or via distinct mechanisms have the greatest potential to overcome resistance; however, novel approaches are also associated with higher attrition and longer timelines. This uncertainty has contributed to the withdrawal from antibiotic programs by many pharmaceutical companies. Genomic approaches have not yielded satisfactory results, in part due to nascent knowledge about unprecedented molecular targets, the challenge of achieving antibacterial activity by lead optimization of enzyme inhibitors, and the limitations of compound screening libraries for antibacterial discovery. Enhanced diversity of compound screening banks, entry into new chemical space, and new screening technologies are currently being exploited to improve hit rates for antibacterial discovery. Antibacterial compound lead optimization faces hurdles associated with the high plasma exposures required for efficacy. Lead optimization would be enhanced by the identification of new antibiotic classes with improved tractability and by expanding the predictability of in vitro safety assays. Implementing multiple screening and target identification strategies is recommended for improving the likelihood of discovering new antibacterial compounds that address unmet needs.

Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-positive antibacterial activity.

Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.