Gram-negative bacteria, especially the ones with multidrug resistance, post dire challenges to antibiotic treatments due to the presence of the outer membrane (OM), which blocks the entry of many antibiotics. Current solutions for such permeability issues, namely lipophilic-cationic derivatization of antibiotics and sensitization with membrane-active agents, cannot effectively potentiate the large, globular, and hydrophilic antibiotics such as vancomycin, due to ineffective disruption of the OM. Here, we present our solution for high-degree OM binding of vancomycin via a hybrid “derivatization-for-sensitization” approach, which features a combination of LPS-targeting lipo-cationic modifications on vancomycin and OM disruption activity from a sensitizing adjuvant. 106- to 107-fold potentiation of vancomycin and 20-fold increase of the sensitizer’s effectiveness were achieved with a combination of a vancomycin derivative and its sensitizer. Such potentiation is the result of direct membrane lysis through cooperative membrane binding for the sensitizer–antibiotic complex, which strongly promotes the uptake of vancomycin and adds to the extensive antiresistance effectiveness. The potential of such derivatization-for-sensitization approach was also supported by the combination’s potent in vivo antimicrobial efficacy in mouse model studies, and the expanded application of such strategy on other antibiotics and sensitizer structures.
Overfeeding causes severe steatosis but not inflammation in goose liver, suggesting existence of protective components. Previous studies have shown that some intestinal microbes and their metabolites damage intestinal structural integrity and function, thus causing inflammation in the development of human and mouse nonalcoholic fatty liver disease. Therefore, this study hypothesizes that intestinal structural integrity of goose is maintained during overfeeding, which may provide goose fatty liver a protective mechanism against inflammation. To test this hypothesis, 48 seventy-day-old healthy Landes male geese were overfed (as overfeeding group) or normally fed (as control group). Blood and intestine (jejunum, ileum, and cecum) samples were harvested on the 12 th and 24 th d of overfeeding. Data showed that goose fatty liver was successfully induced by 24 d of overfeeding. Hematoxylin-eosin staining analysis indicated that the arrangement of villi and crypts in the intestine was orderly, and the intestinal structure was intact with no pathological symptoms in the 2 groups. Enzyme-linked immunosorbent assay and quantitative PCR analysis indicated no significant differences in the expression of tight junction and inflammation-related genes as well as plasma lipopolysaccharide concentration between the groups. Ileal hypertrophy and cecal atrophy were observed in the overfed vs. control geese, probably because of change of sphingolipid metabolism. Activation of apoptotic pathway may help cecum avoid necrosis-induced inflammation. In conclusion, healthy and intact intestine provides a layer of protection for goose fatty liver against inflammation. Sphingolipid metabolism may be involved in the adaptation of ileum and cecum to overfeeding. The hypertrophy of ileum makes it an important contributor to the development of goose fatty liver. The atrophy and decline in the function of cecum may be caused by apoptosis induced by overfeeding.
Fatty liver hemorrhagic syndrome ( FLHS ), usually occurring in hens in the late laying period, can lower egg yield and even cause death. Similar to nonalcoholic fatty liver disease in humans, FLHS may begin with simple hepatic steatosis. It is known that gut microbiota is important to the development of nonalcoholic fatty liver disease, but the relationship between FLHS and gut bacteria remains unclear. In this study, bacteria compositions in the ileum and cecum were determined by 16S rDNA sequencing analysis in the groups of hens with vs. without hepatic steatosis (average liver fat contents were 0.34 mmol/g protein or 2.6% vs. 0.84 mmol/g protein or 6.0%). These hens were in the 2 tails of the liver fat content distribution with each tail accounting for 10% of the test population containing 90 66-wk-old healthy Rhode Island Red laying hens raised under routine feeding regimen. The results showed that liver weight but not the weights of the body, heart and abdominal fat were significantly different between the groups. Moreover, bacterial diversity was not significantly different between the groups, but bacterial diversity in the cecum was higher than that in the ileum. Proteobacteria was the most dominant phylum in the ileum, whereas Proteobacteria, Firmicutes, and Bacteroidetes were the most dominant phyla in the cecum. Some bacteria were common to the ileum and cecum, but some were unique. Furthermore, some bacteria were significantly different in abundance between the groups, that is the group without hepatic steatosis had more bacteria inhibiting host energy absorption or benefiting intestinal health, whereas the group with hepatic steatosis had more conditionally pathogenic or harmful bacteria. In conclusion, hepatic steatosis in laying hens is associated with intestinal bacterial composition (bacterial abundance) but not bacterial diversity. The identified common and unique bacteria are related to the functional characteristics of the ileum and cecum. The decrease of beneficial bacteria and the increase of harmful bacteria in the intestine of laying hens may increase FLHS incidence by promoting hepatic steatosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.