Hybrid Molecules Designed to Enhance Antibiotic Activity

Period of Performance: 03/01/2000 - 02/28/2002

$146K

Phase 1 SBIR

Recipient Firm

Glsynthesis, Inc.
Worcester, MA 01605
Principal Investigator

Abstract

This project aims to increase the therapeutic potential of a Gram-positive specific antimicrobial by simultaneously increasing potency and water solubility. This will be accomplished through the synthesis of a series of bifunctional molecules in which an established Gram-positive specific DNA polymerase III inhibitor is attached to a weak intercalator through a linker of varying lengths in the expectation of creating a hybrid molecule capable of binding to DNA by both hydrogen bonding and intercalation. For each compound, a pharmacological profile will be obtained that will be predictive of Gram-positive specific antibiotic potential and potential toxicity. Compounds emerging from phase I with higher in vitro potency and water solubility than the parent inhibitor and low toxicity will be further analyzed during phase II for in vivo potency and toxicity. The major aim of this project is the emergence, by the end of phase II, of pre-clinical candidates for the treatment of bacterial infections by antibiotic resistant Gram-positive organisms such as Staphylococcus aureus and Enterrococcus fecalis with the ultimate goal of filing an Investigational New Drug (IND) application with the FDA. PROPOSED COMMERCIAL APPLICATIONS: A Gram-positive specific DNA polymerase III inhibitor demonstrating increased potency and water solubility over existing inhibitors would have enormous therapeutic and commercial potential as a "last-ditch" antibiotic to treat organisms with resistance to currently marketed antibiotics such as oxacillin and vancomycin.