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Abstract

Grant Number:	5R44GM060828-03
PI Name:	WRIGHT, GEORGE E.
PI Email:	george.wright@glsynthesis.com
PI Title:	PRESIDENT
Project Title:	Hybrid Molecules Designed to Enhance Antibiotic Activity

Abstract: There is a crisis in the management of diseases caused by multi- antibiotic resistant strains of Gram-positive bacteria. This work will result in the development of new antibiotic drugs acting on a novel target. It is both technologically innovative and highly relevant to human health. Phase I of this project served to increase the therapeutic potential of a Gram-positive specific anti-microbial by simultaneously increasing its potency and water solubility. This was accomplished through the synthesis and evaluation of a series of potentially bifunctional molecules that combine an established Gram-positive specific DNA polymerase IIIC inhibitor with another molecule known to interact with DNA. A lead compound has been identified and Phase II of this program will focus on conducting the experiments necessary to declare a form of this compound as a "candidate for development". The research plan for Phase II combines: (i) scale-up of the synthesis of the lead compound; (ii) synthesis of a series of salts to enhance water solubility; (iii) evaluation of salts and formulations of the lead compound in vitro; (iv) evaluation of acute toxicity and pharmacokinetics of promising salts and formulations; and (v) testing of promising salts and formulations in in vivo models of Gram-positive bacterial infection. Preclinical studies of a defined candidate for development emerging from Phase II will be undertaken by Microbiotix Inc. together with their development partner Shire BioChem Inc. PROPOSED COMMERCIAL APPLICATIONS: The drug industry is aggressively seeking to develop antibiotics that attack novel targets. A Gram-positive specific antibiotic emerging from Phase II effective against multi-antibiotic resistant bacteria would have enormous therapeutic and commercial potential initially as a parenteral drug in the treatment of hospitalized patients and eventually as a first line antibiotic in the treatment of Gram-positive infection.

Thesaurus Terms:
DNA directed DNA polymerase, antibiotic, drug design /synthesis /production, drug screening /evaluation, enzyme inhibitor, gram positive bacteria, uracil
chemical synthesis, cytotoxicity, hydrazine, mutagen, water solubility
tissue /cell culture

Institution:	GLSYNTHESIS, INC.
	1 INNOVATION DR
	WORCESTER, MA 01605
Fiscal Year:	2003
Department:
Project Start:	01-MAR-2000
Project End:	30-APR-2004
ICD:	NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
IRG:	ZRG1

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