title: Permeation Enhancement to Improve Antibiotic Transit Across Intestinal Barriers
Creators: name: McMahon, Finn
Publisher: name: Griffith University
Year: 2024
Subjects: subject: permeation enhancement
subject: CAI-1
subject: Caco-2

description: Antimicrobial resistance is a global healthcare problem that negatively affects patient outcomes and increases the financial healthcare burden. Prolonged hospital stay has a high risk associated with contracting nosocomial infections, with a significant number of nosocomial infections being multi-drug resistant. Intravenous (IV) antibiotics significantly contribute to developing and transmitting antimicrobial-resistant infections within hospitals. IV antibiotics are necessary in the hospital setting to address severe infections; however, they are often overused or misused due to their ease of use and administration. Furthermore, many antibiotics have selective administration pathways, such as IV only, due to their inability to transit through the digestive system and intestinal tract or high inter-patient variability. Permeation enhancement is a proposed method for increasing the bioavailability of oral medication. If a permeation enhancer can be successfully paired with antibiotics, then previously non-orally available antibiotics could be administered orally. This has the potential to decrease the reliance on IV antibiotics and decrease antimicrobial-resistant infections. Several classes of permeation enhancers have previously been investigated, with some medium chain fatty acid permeation enhancers being approved for clinical use. However, these permeation enhancers are targeted at increasing the diffusion of peptide molecules and have only shown a low single-digit increase in diffusion in vivo. Previous analysis on cross-kingdom signalling and cell metabolism of quorum sensing molecules has shown significant changes in barrier resistance and permeability in vitro at concentrations much lower than medium chain fatty acid permeation enhancers. This indicates a potential new class of permeation enhancers or a backbone structure that can be used to develop a new class of permeation enhancers. Based on previous research, it was hypothesised that cholera autoinducer-1 (CAI-)1 and 3-oxo-dodecanol Acyl-homoserine lactone (3-oxo-C12 AHL) would be successful as novel permeation enhancers. CAI-1 and 3-oxo-C12 AHL are quorum-sensing molecules that can disrupt a monolayer cell barrier at low micromolar concentrations. Although their effectiveness at disrupting a monolayer barrier has been demonstrated, many unknowns remained that would confirm their effectiveness and suitability as novel permeation enhancers. This included their effective dose range, onset of action, transience, and cytotoxicity. Thus, the aim of this study was to determine if CAI-1 and 3-oxo-C12 AHL function as novel permeation enhancers. This was an in vitro quantitative experimental study using the intestinal Caco-2 cell line in the Transwell® model. Barrier permeability changes were measured using transepithelial electrical resistance (TEER) and the apparent permeability (Papp) of fluorescein and antibiotics (flucloxacillin and ampicillin). Success as a permeation enhancer was determined by the effective concentration, onset of action, cell recovery, and cytotoxicity. For CAI-1, as well as analysing an effective dose range, enantiomeric-specific differences were measured. Analyses for the onset of action, barrier recovery and cytotoxicity assays were done for CAI-1 and 3-oxo-C12 AHL. [...]