Epoxy-tiglianes for the treatment of chronic wounds, multi-drug resistant bacteria and oral infections

Xue, Wenya 2022. Epoxy-tiglianes for the treatment of chronic wounds, multi-drug resistant bacteria and oral infections. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Bacterial resistance to antibiotic and antimicrobial therapy represents a significant global health challenge, resulting from genotypic and phenotypic adaption. Whilst many novel antimicrobial approaches to overcome this resistance have been described, few have been of practical clinical use. A repeated observation, in companion animals treated with the anti-tumour agent tigilanol tigliate (EBC46: Stelfonta®) was the induction of healing of infected skin wounds which were previously unresponsive to conventional therapy. Nothing was understood about the magnitude, or potential mechanisms of this antibacterial activity. Using a range of epoxy-tigliane structures (EBC-1013, EBC-46 and EBC-147), with varying biological activity (in stimulating Protein kinase C [PKC]), the effects of these agents on bacteria and bacterial biofilms were studied in vitro. Susceptibility testing against a range of Gram-negative and Gram-positive bacteria was performed using minimum inhibitory concentration (MIC) and minimum biofilm eradication concentration (MBEC) assays. Direct interactions between the epoxy-tiglianes and the bacterial cell surface (lipopolysaccharide [LPS] and lipoteichoic acid [LTA]) were initially studied using circular dichroism (CD) spectroscopy and membrane permeabilisation assays and then using in vitro models of biofilm formation and disruption using confocal laser scanning microscopy (CLSM) and COMSTAT image analysis. MICs were determined (Gram-positive > Gram-negative) and anti-biofilm effects against Gram-negative and Gram-positive biofilms; these effects were shown to be related to alterations in bacterial cell surface hydrophobicity and inhibition of swarming motility. The effects were apparent against bacteria from both chronic wound infections and bacteria in dental, biofilm-related disease (S. mutans and P. gingivalis), and biofilms on relevant surfaces (titanium). In the chronic wound setting, analysis of EBC-treated P. aeruginosa, revealed the effects of EBC-1013 were related to quorum sensing (QS) dysregulation, with inhibition of swarming motility and virulence factor production (EBC-1013>EBC-46>EBC-147). Direct anti-biofilm activity was demonstrated using minimum biofilm eradication concentration (MBEC) assays and the potential for EBC-1013 as an antibiotic adjuvant tested. Using epoxy- V tiglianes and selected antibiotics on multidrug-resistant (MDR) bacteria including colistin resistant (COLR) mcr E. coli, synergy was demonstrated in MBEC and COMSTAT modelling. These results provide the first insight into the role of epoxy-tiglianes as a potential (topical) treatment for use against chronic wound and periodontal biofilms. The lead candidate EBC-1013 is now development for clinical use.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Dentistry
Date of First Compliant Deposit:	16 August 2022
Last Modified:	05 Jan 2024 06:21
URI:	https://orca.cardiff.ac.uk/id/eprint/151970

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