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|Title:||DISCOVERY AND DEVELOPMENT OF NOVEL ANTI-MICROBIAL THERAPEUTICS||Authors:||CHOW JENG YEONG||Keywords:||Anti-Microbial Therapeutics,Plant Root Exudates,Type III Polyketide Synthases,Combinatorial Biosynthesis,Quorum Sensing,N-acyl Homoserine Lactonases||Issue Date:||9-Nov-2012||Citation:||CHOW JENG YEONG (2012-11-09). DISCOVERY AND DEVELOPMENT OF NOVEL ANTI-MICROBIAL THERAPEUTICS. ScholarBank@NUS Repository.||Abstract:||To achieve a leading edge in the battle against antibiotic-resistant pathogens, novel therapeutic strategies have to be developed. In this project three different approaches were explored for their feasibility in the attenuation of bacterial virulence. The first method involves an attempt to isolate and characterize an anti-microbial compound from a previously unexplored niche; the root exudate of rice plants. In the second approach, a type III polyketide synthase from rice was cloned for use in combinatorial biosynthesis. Precursor-directed biosynthesis and structure-based engineering of the enzyme was used to generate a library of polyketides. Coupled with an anti-microbial screen, we identified bisnoryangonin as an anti-microbial polyketide specific against various Gram-positive bacteria. The last approach explored the development of a class of enzymes known as AHL-lactonases for the disruption of quorum-sensing in Gram-negative pathogens. Directed evolution of a thermostable AHL-lactonase allowed us to identify enhanced mutants with increased catalytic activity and substrate range. The therapeutic potential of these enzymes were also demonstrated with their ability to disrupt the biofilm formation of Acinetobacter baumannii.||URI:||http://scholarbank.nus.edu.sg/handle/10635/47514|
|Appears in Collections:||Ph.D Theses (Open)|
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