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Abstract

Grant Number:	1R43AI053929-01
PI Name:	BROWN, MARK J.
PI Email:	mbrown@echelon-inc.com
PI Title:
Project Title:	Screen for Isoprenoid Production in M. tuberculosis

Abstract: DESCRIPTION (provided by applicant): Isoprenoid compounds form a large ubiquitous class of natural products that fulfill a wide variety of essential cellular functions in all living organisms. In eukaryotes, isoprenoid compounds are synthesized by a mevalonate (MVA) dependent pathway. However, in many bacteria, these compounds are synthesized by an alternative, MVA-independent route whose first committed intermediate is 2-methylerythritol 4-phosphate (MEP). Both pathways converge at isopentenyl diphosphate (IPP) and subsequent steps are similar in all organisms. Since the MEP pathway is absent in mammals, it is considered an attractive target for the development of novel antibiotics. The pathogen, M. tuberculosis belongs to the MEP pathway class of organisms. The applicants will prepare a transgenic bacterial E. coli host cell whose genome contains disruptions in a first endogenous gene in the MEP pathway and a second endogenous gene which is located downstream of the first gene in the MEP pathway. A transgene from M. tuberculosis that functionally replaces the disrupted downstream gene will be cloned into the cell. The growth of the host cell in the presence of test agent is then compared to a control culture to determine the activity of the test agent. Where the test agent renders the bacterial host cell nonviable on media containing a chemical supplement to relieve the 1-deoxy-D-xylulose-5-phosphate (DXP) block and viable on the media containing MVA indicates that the test agent has the potential to be an effective antibacterial against M. tuberculosis.

Thesaurus Terms:
Mycobacterium tuberculosis, biochemistry, biological product, chemical structure function, genetic screening, isoprenoid, sugar alcohol
transferase
Escherichia coli, chemical registry /resource, high throughput technology, molecular cloning

Institution:	ECHELON BIOSCIENCES, INC.
	675 ARAPEEN DR, STE 302
	SALT LAKE CITY, UT 84108
Fiscal Year:	2003
Department:
Project Start:	15-MAY-2003
Project End:	14-MAY-2004
ICD:	NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
IRG:	ZRG1

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