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

Arun Sharma, Jacek Krzeminski, Volkmar Weissig, John P. Hegarty, David B. Stewart

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Conventional antibiotics for C. 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 of E. coli, B. fragilis, and E. faecalis, and against C. difficile by “loading” CABVs with 25-mer antisense oligonucleotides (ASO) targeting dnaE. 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 on C. difficile growth in culture (MIC90 ≥ 160 µM). While APDE-8 and CODE-9 nanocomplexes demonstrated high MIC 90 against C. difficile cultures (>300 µM), CYDE-21 nanocomplexes demonstrated MIC 90 at CABV concentrations of 19 µM. Empty CABVs formed from APDE-8 and CODE-9 had virtually no effect on E. coli, B. fragilis, and E. faecalis across all tested concentrations, while empty CYDE-21 demonstrated MIC 90 of >160 µM against E. coli and >40 µM against B. fragilisand E. faecalis. Empty CABVs have limited antibacterial activity and they can deliver an amount of ASO effective against C. 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.

Original languageEnglish (US)
Pages (from-to)713-721
Number of pages9
JournalJournal of Antibiotics
Volume71
Issue number8
DOIs
StatePublished - Aug 1 2018

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Antisense Oligonucleotides
Microbiota
Escherichia coli
Infection
Dysbiosis
Anti-Bacterial Agents
Caco-2 Cells
Cell Culture Techniques
Bacteria
Growth
bolaamphiphile
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery

Cite this

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title = "Cationic amphiphilic bolaamphiphile-based delivery of antisense oligonucleotides provides a potentially microbiome sparing treatment for C. difficile",
abstract = "Conventional antibiotics for C. 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 of E. coli, B. fragilis, and E. faecalis, and against C. difficile by “loading” CABVs with 25-mer antisense oligonucleotides (ASO) targeting dnaE. 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 on C. difficile growth in culture (MIC90 ≥ 160 µM). While APDE-8 and CODE-9 nanocomplexes demonstrated high MIC 90 against C. difficile cultures (>300 µM), CYDE-21 nanocomplexes demonstrated MIC 90 at CABV concentrations of 19 µM. Empty CABVs formed from APDE-8 and CODE-9 had virtually no effect on E. coli, B. fragilis, and E. faecalis across all tested concentrations, while empty CYDE-21 demonstrated MIC 90 of >160 µM against E. coli and >40 µM against B. fragilisand E. faecalis. Empty CABVs have limited antibacterial activity and they can deliver an amount of ASO effective against C. 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.",
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Cationic amphiphilic bolaamphiphile-based delivery of antisense oligonucleotides provides a potentially microbiome sparing treatment for C. difficile. / Sharma, Arun; Krzeminski, Jacek; Weissig, Volkmar; Hegarty, John P.; Stewart, David B.

In: Journal of Antibiotics, Vol. 71, No. 8, 01.08.2018, p. 713-721.

Research output: Contribution to journalArticle

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