Mangrolide A, A Novel Marine Derived Polyketide with Selective Antibiotic Activity
The ability of nature to produce complex, biologically active compounds has inspired researchers throughout history. The isolation of these molecules has been instrumental in the discovery of many medicinal compounds, especially to combat infections caused by pathogenic bacteria. Antibiotic resistance is a major challenge faced in hospitals today, and there is an urgent need for new antibiotics. The "Golden Age" of antibiotic development was spurred by compounds isolated from terrestrial bacteria. Unfortunately, the rate of discovery of new compounds has decreased and new techniques and sources are required. The marine environment contains novel natural product-producing bacteria and has yielded new compounds with potent activity. This dissertation represents work towards new antibiotic discovery from marine natural products. Chapter 1 provides an introduction to marine natural product research with a focus on new developments in the field. Chapter 2 describes the isolation and characterization of a new macrolide, mangrolide A, which was discovered though a phenotypic screen against Burkholderia cepacia. Mangrolide A has selective activity against gram negative bacteria. The determination of the absolute stereochemistry of mangrolide A is described in chapter 3. In chapter 4, a new method to increase the production of mangrolide A and activate cryptic metabolite pathways in SNA-18 is applied and results in a new mangrolide analogue. Chapter 5 finishes with the results of a screen using an efflux deficient strain of Pseudomonas aeruginosa. This experiment led to the isolation of the known natural products alldimycin A-C and new ammosamide analogues.