The present study investigated the utility of in vitro lipolysis performance indicators drug solubilization and maximum supersaturation ratio (SR(M)) for their predictive use for the in vivo performance in a minipig model. The commercial Lipanthyl formulation and a series of LbDDS based on identical self-nanoemulsifying drug delivery systems (SNEDDS) containing 200 mg of fenofibrate, either dissolved or suspended, were subjected to combined gastric (pH 2) and intestinal (pH 6.5) in vitro lipolysis. Based on the solubilization profiles and SRM the rank-order SNEDDS (75% drug load) > super-SNEDDS (150% drug load, dissolved) = SNEDDS suspension (150% drug load, partially suspended) > Lipanthyl was established, with an increased likelihood of drug precipitation above SR(M) > 3. The in vitro performance, however, was not reproduced in vivo in a minipig model as the mean plasma concentration over time curves of all LbDDS were comparable, independent of the initial physical state of the drug. There was no correlation between the area under the solubilization-time curves (AUC(in vitro)) of the intestinal step and the AUC(in vivo). The study suggests careful interpretation of in vitro performance criteria and revision of LbDDS optimization towards increased solubilization.

Staphylococcus aureus is a major cause of nosocomial infections and secretes a diverse spectrum of virulence determinants as well as forms biofilm. The emergence of antibiotic-resistant S. aureus highlights the need for alternative forms of therapeutics other than conventional antibiotics. One route to meet this need is screening small molecule derivatives for potential anti-infective activity. Using a previously optimized C. elegans – S. aureus small molecule screen, we identified a benzimidazole derivative, UM-C162, which rescued nematodes from a S. aureus infection. UM-C162 prevented the formation of biofilm in a dose-dependent manner without interfering with bacterial viability. To examine the effect of UM-C162 on the expression of S. aureus virulence genes, a genome-wide transcriptome analysis was performed on UM-C162-treated pathogen. Our data indicated that the genes associated with biofilm formation, particularly those involved in bacterial attachment, were suppressed in UM-C162-treated bacteria. Additionally, a set of genes encoding vital S. aureus virulence factors were also down-regulated in the presence of UM-C162. Further biochemical analysis validated that UM-C162-mediated disruption of S. aureus hemolysins, proteases and clumping factors production. Collectively, our findings propose that UM-C162 is a promising compound that can be further developed as an anti-virulence agent to control S. aureus infections.