Cationic amphiphilic bolaamphiphile-based delivery of antisense oligonucleotides provides a potentially microbiome sparing treatment for C. difficile. (August 2018)

• Record Type: Journal Article
• Authors: Sharma, Arun; Krzeminski, Jacek; Weissig, Volkmar; Hegarty, John; Stewart, David
• Is Part Of: Journal of antibiotics. Volume 71:Number 8(2018:Aug.)
• Page Start: 713
• Page End: 721
• Publication Date: 2018-08
• Subjects: Antibiotics -- Periodicals; 615.329
• DOI: 10.1038/s41429-018-0056-9
• Languages: English
• ISSNs: 0021-8820

Abstract

Abstract Conventional antibiotics forC. difficile infection (CDI) have mechanisms of action without organismal specificity, potentially perpetuating the dysbiosis contributing to CDI, making antisense approaches an attractive alternative. Here, three (APDE-8, CODE-9, and CYDE-21) novel cationic amphiphilic bolaamphiphiles (CABs) were synthesized and tested for their ability to form nano-sized vesicles or vesicle-like aggregates (CABVs), which were characterized based on their physiochemical properties, their antibacterial activities, and their toxicity toward colonocyte (Caco-2) cell cultures. The antibacterial activity of empty CABVs was tested against cultures ofE. coli, B. fragilis, andE. faecalis, and againstC. difficile by "loading" CABVs with 25-mer antisense oligonucleotides (ASO) targetingdnaE . Our results demonstrate that empty CABVs have minimal colonocyte toxicity until concentrations of 71 µM, with CODE-9 demonstrating the least toxicity. Empty CABVs had little effect onC. difficile growth in culture (MIC90 ≥ 160 µM). While APDE-8 and CODE-9 nanocomplexes demonstrated high MIC90 againstC. difficile cultures (>300 µM), CYDE-21 nanocomplexes demonstrated MIC90 at CABV concentrations of 19 µM. Empty CABVs formed from APDE-8 and CODE-9 had virtually no effect onE. coli, B. fragilis, andE. faecalis across all tested concentrations, while empty CYDE-21 demonstrated MIC90 of >160 µM againstE. coli and >40 µM againstB. fragilis andE. faecalis . Empty CABVs have limited antibacterial activity and they can deliver an amount of ASO effective againstC. difficile at CABV concentrations associated with limited colonocyte toxicity, while sparing other bacteria. With further refinement, antisense therapies for CDI may become a viable alternative to conventional antibiotic treatment.