Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections
Annual rept. 26 Sep 2011-25 Sep 2012
HAUPTMAN-WOODWARD MEDICAL RESEARCH INST BUFFALO NY
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We are combining two parallel efforts to explore new targets and pathways in A. baumannii. We hypothesize that two proteins involved in aromatic amino acid and metabolite biosynthesis are essential and are valid targets for development of inhibitors as potential antibiotics. We additionally hypothesize that a novel natural product is produced by A. baumannii that may play a role in pathogenesis or virulence. Goal 1. We aim to validate two protein targets that have been identified through genetic screening as essential targets in A. baumannii. These targets will be biochemically and structurally characterized, and will be screened in silico for potential fragment-based ligands that could bind to the enzyme active site. Conservation and prevalence of the targeted genes for goal 1 confirm essentiality and cloning, expression, purification, and preliminary crystallization was completed during year 1. Goal 2. We will characterize biochemically a novel natural product biosynthetic pathway to identify a new secondary metabolite and characterize the phenotype of a deletion strain that is unable to produce this compound. All genes for goal 2 have been cloned and catalytic proteins have been purified. Functional reconstitution of this pathway was initiated, identifying potential natural product building blocks. A structure of one protein has been determined.
- Medicine and Medical Research