Date of Award

11-2009

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Marc Devocelle, PhD

Keywords

Drug Resistance, Clostridium Difficile

Abstract

The bacterium Clostridium difficile is the most prominent cause of hospital-acquired diarrhoea and disease of the large bowel. Clostridium difficile produces toxins that damage the colonic epithelium, causing inflammatory colitis that may be fatal. The treatment strategy against Clostridium difficile is currently mainly limited to a course of antibiotics metronidazole or the cyclic peptide vancomycin. However, due to emergence of antibiotic resistance, there is a desire for new antibiotics. Host-defence or antimicrobial peptides offer a promising approach to overcoming antibiotic resistance. By interacting selectively with non-specific microbial components, antimicrobial peptidcs evade evolution of microbial resistance. A challenge to the clinical development of therapeutic peptides is site-specific drug delivery. Herein, a novel strategy for the delivery of therapeutic antimicrobial peptides as prodrugs that release active peptide and mutual-drug anti-inflammatory agents upon metabolism by clostridial reductase enzyme for the treatment of Clostridium difficile infection and inflammatory colitis has been developed, whereby antimicrobial peptides are protected at the alpha-amino terminal either by an azo bond to the anti-inflammatory agent 4-aminophenylacetic acid facilitated by an alpha-aminoisobutyric acid linker that increases the antimicrobial potency of the peptides, or by a benzyl carbamate linker bearing either a nitro or azo, bound to anti-inflammatory agent 5-aminosalicylic acid, as a reducible para substituent. The prodrug peptides and antibiotic peptides modified at the amino terminal by alpha-aminoisobutyric acid are prepared and evaluated for antimicrobial susceptibility against pathogenic bactcria Clostridium difficile and Staphylococcus aureus by determination of minimum inhibitory concentrations. The reduction of the prodrug linker containing 5-azosalicylic acid by the presence of Clostridium difficile is demonstrated spectrophotometrically.These results confirm the feasibility of this novel approach to delivery of antimicrobial peptides and anti-inflammatory agents for the treatment of Clostridium difficile infection and associated colitis.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

19,546 KB

Comments

A thesis submitted to the Royal College of Surgeons in Ireland for the degree of Doctor of Philosophy from the National University of Ireland in 2009.

Share

COinS