| dc.description.abstract | The increasing threat of antibiotic resistant pathogens is a major problem in the management of infectious diseases, making it imperative that new antibiotics to combat them are discovered and sourced. However, limiting work to merely discovering these novel antibiotics is far too narrow of a scope. It is equally important to understand how the biochemistry and production of these secondary metabolites is regulated. Furthermore, a better understanding of the bioactivity and structure of novel variants of secondary metabolites may lead to the identification of products with enhanced properties, such as improved spectrum of activity or reduced minimum inhibitory concentrations.
Using a member of the Burkholderia cepacia complex, Burkholderia contaminans MS14, my thesis studies have been aimed at identifying novel antimicrobial factors and to gain a better understanding of the antimicrobial secondary metabolites the bacterium is capable of producing. The Burkholderia genus is highly conserved; therefore many of the insights gleaned from its study could be applied to other members of its genus. This includes the more virulent strains such as Burkholderia cepacia and Burkholderia pseudomallei. My work led to the identification of a novel antibacterial produced by B. contaminans MS14. In these studies, it was discovered that MS14 also produces ornibactin, a powerful siderophore. Siderophores are commonly associated with iron acquisition. However, the most interesting aspect was not the production of ornibactin, but its role in regulating the production of a separate antibacterial product. Thus we learned that ornibactin, rather than just being an additional product with minor antibacterial properties, has a direct effect on the antimicrobial capabilities of B. contaminans MS14. My studies clearly show an alternative function for this siderophore, as knockout strains that lacked the ability to make ornibactin completely lost bactericidal activity. While this antimicrobial product proved difficult to isolate, I was able to investigate and report several of its inherent properties, such as its estimated size, polarity, and stability. Interestingly, this product is highly resistant to common forms of damage, such as temperature and pH. However, direct UV exposure resulted in the destruction of this antibiotic, giving clues into its physical structure.
Occidiofungin is a novel lipopeptide that is a potent anticandidal fungicide and exhibits its mode of action by binding to actin, resulting in apoptosis. However, in addition several variants are also produced. Studies on the isolation of these different variants of occidiofungin have led to the discovery of a new product. Due to their potency against opportunistic pathogens of both humans and plants, these variants are possible candidates for medical or agricultural applications. In addition to the known variants, the discovery of a novel variant and the further structural elucidation of the compound using nuclear magnetic resonance, suggests that the non-ribosomal peptide synthetase (NRPS) module for diamino butyric acid has some promiscuity for other amino acids. Additional information pertaining to its spectrum of activity and anticandidal properties has been determined. | en |
