Oral Delivery of Cholic Acid-Derived Amphiphile Helps in Combating Salmonella-Mediated Gut Infection and Inflammation

Abstract

A major impediment to developing effective antimicrobials against Gram-negative bacteria like Salmonella is the ability of the bacteria to develop resistance against existing antibiotics and the inability of the antimicrobials to clear the intracellular bacteria residing in the gastrointestinal tract. As the critical balance of charge and hydrophobicity is required for effective membrane-targeting antimicrobials without causing any toxicity to mammalian cells, herein we report the synthesis and antibacterial properties of cholic acid-derived amphiphiles conjugated with alkyl chains of varied hydrophobicity. Relative to other hydrophobic counterparts, a compound with hexyl chain (6) acted as an effective antimicrobial against different Gram-negative bacteria. Apart from its ability to permeate the outer and inner membranes of bacteria; compound 6 can cross the cellular and lysosomal barriers of epithelial cells and macrophages and kill the facultative intracellular bacteria without disrupting the mammalian cell membranes. Oral delivery of compound 6 was able to clear the Salmonella-mediated gut infection and inflammation, and was able to combat persistent, stationary, and multi-drug-resistant clinical strains. Therefore, our study reveals the ability of cholic acid-derived amphiphiles to clear intracellular bacteria and Salmonella-mediated gut infection and inflammation.

Foliar Application or Seed Priming of Cholic Acid-Glycine Conjugates can Mitigate/Prevent the Rice Bacterial Leaf Blight Disease via Activating Plant Defense Genes

“…However, CA or CAGCs have not been exploited in agriculture even though they are found to be abundant in soil. Our studies showed that C6 CAGC with hexyl chain is bactericidal against Xoo and fungicidal against R. solani by disrupting its membranes as reported in other microbial systems (Yadav et al, 2019). CAGCs degrade and reduce >60% biofilm formation at lower concentrations that inhibit the ability of Xoo to secrete Xanthomonadin required for the attachment to the leaf surface, Xoo viability, and pathogenesis (Park et al, 2009;He et al, 2011;Yu et al, 2015).…”

“…We synthesized nine different CAGCs as reported previously (Yadav et al, 2019). A single colony of Xoo (PXO99) was cultured in NB medium at 28 • C with shaking at 180 rpm.…”

“…We used nine CAGCs, where CA was modified at the carboxylic acid position with different alkyl groups (methyl to dodecyl) using ester bonds, and three glycine moieties were tethered at three hydroxyl groups (Figure 1A) (Yadav et al, 2019). The antimicrobial activity of these nine CAGCs was tested against Xoo, and MIC 99 of CAGCs that are required to kill 99% of bacteria were measured.…”

“…As CA is a naturally occurring biomolecule of the human body, CA-derived biodegradable molecules can provide a suitable alternative to mitigate plant pathogens. Our earlier studies have shown that cholic acid-glycine conjugates (CAGCs) are potent broad-spectrum antimicrobials over the naturally occurring bile acids (Yadav et al, 2019.…”

DeSUMOylase SENP7-Mediated Epithelial Signaling Triggers Intestinal Inflammation via Expansion of Gamma-Delta T Cells

“…Second, it highlights the possibility of using SENP7 and delivery vehicles similar to those used in the current study as a tool for combating intestinal inflammatory conditions not restricted to IBD. A dysregulated SUMOylome has been seen in several different forms of intestinal inflammation, including those resulting from infectious diseases (Ribet et al, 2010;Fritah et al, 2014;Verma et al, 2015;Sidik et al, 2015;Yadav et al, 2019). Lastly, gut-specific SENP7 knockdown or knockout may also have an effect on the composition of intestinal microbiota, an aspect that cannot be ignored if this will be evolved as a tool for intervention against inflammation.…”