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.
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.
| Zhi, Chengxin; Long, Zheng-Yu; Manikowski, Andrzej et al. (2006) Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors. J Med Chem 49:1455-65 |
