The increasing prevalence of drug resistant bacteria has resulted in a dire need for new approaches to antimicrobials. In particular, the discovery and development of small molecules that are not as predisposed to selective pressure and, as a consequence, offer fewer opportunities for the development of resistance, is a topic of current interest and one where we believe we can help to make a difference. This proposal outlines our program is concentrated on developing novel scaffolds aimed at disrupting bacterial communication and virulence, especially in gram-positive bacteria. We propose to study two natural product lead molecules over the course of four phases that combine the development of organic chemistry methodology with total synthesis and SAR. Concurrent to these efforts will be studies whose goals are to ascertain the ability of our synthetic compounds to control virulence. The choice of inhibitors to begin our studies has taken into account the accessibility of the small molecule targets using efficient and novel chemical synthesis methodology, the activity of the targets against virulence targets, including sortase A, and the ability of the compounds to inhibit biofilm formation and to disrupt preformed biofilms. Our lead structures are discorhabdin Z, a pyrroloiminoquinone natural product that comes from the marine sponge, Sceptrella sp. and taxodone, a diterpene natural product of the abietane family that comes from the roots of the sage Salvia austriaca. Both of these agents will synthesized using a unique and stereoselective bis-aryl alkene photochemical electrocyclization reaction sequence. We will continue to develop and optimize the photoelectrocyclization reactions over the course of the proposed efforts. In the third phase of the program we will generate analogs of discorhabdin Z and taxodone aimed at enhancing their virulence activity while tempering, for the discorhabdins, their cytotoxicity. The final phase of the work proposed here will be carried out in collaboration with the University of Utah Medicinal Chemistry Core Facility and will target the development of a panel of assays aimed at gathering information about the antibiotic activity, anti-biofilm activity, sortase A activity, and toxicity of all of our synthetic compounds.
The proposed studies promise to better understand and develop novel therapies for the treatment of bacterial infections and are critical to the mission of the NIH and public health. We are specifically interested in developing novel and innovative therapies that are less susceptible to selective pressure and the development of bacterial resistance as a consequence of their ability to disrupt bacterial communication and virulence.
