HYBRID MOLECULES DESIGNED TO ENHANCE ANTIBIOTIC ACTIVITY

here 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.