Date of Award

2010

Document Type

Doctoral Thesis

Degree Name

Doctor of Philosophy

Department

Department of Biological Sciences

First Advisor

Dr. Jim O'Mahony

Abstract

Despite the success of anti-mycobacterial drugs over the past 70 years, mycobacterial disease, particularly tuberculosis is still responsible for millions of deaths worldwide. Additionally, the emergence of Multidrug Resistant (MDR-TB) and Extensively Drug Resistant (XDR-TB) Tuberculosis throughout the world has motivated calls by the World Health Organization for novel mycobacterial drugs, vaccines and diagnostic tests. Consequently, this study sought to identify and evaluate the efficacy of a range of anti-mycobacterial compounds against a representative cohort of pathogenic mycobacterial species. The development and employment of the rapid, robust and inexpensive microtitre alamarBlue assay (MABA) facilitated the assessment of a vast array of anti-mycobacterial compounds including chemically and biologically derived drug analogues of pre-existing anti-mycobacterial agents.

While existing anti-mycobacterial drugs are effective when administered a cocktail, continuous research and development of novel classes of anti-mycobacterial is of paramount importance. In particular, there is significant scope for the implementation of gene-encoded antimicrobials for therapeutic application. Bio-engineering of these peptides such as nisin and lacticin 3147 facilitates the identification of more active variants of the natural peptide. In this regard, three nisin clones (nisin S, nisin T and nisin V) were identified as possessing enhanced anti- mycobacterial activity. Mycobacterial drug resistance to such anti- mycobacterial drugs was also investigated. Using in silico analysis the role of drug efflux pumps as a mechanism of intrinsic resistance was investigated, resulting in the identification of novel drug efflux pumps in M. avium subsp. paratuberculosis.

Access Level

info:eu-repo/semantics/openAccess

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