Research Project
8986745
DESCRIPTION (provided by applicant): Chronic wounds that fail to respond to traditional therapeutic interventions afflict millions of people each year, and direct costs associated with treating these wounds are estimated at $10-25 billion annually in the U.S. alone. Eradication of pathogenic bacteria that have colonized chronic wounds is complicated by the propensity of these bacteria to form biofilms. A biofilm consists of a community of bacteria encompassed by an extracellular matrix which efficiently resists the action of antibiotics and the host immune response. Bacteria in the biofilm state are approximately one-thousand times more resistant to antibiotics, and there are currently no reliable therapeutic strategies available for dispersing pr-formed biofilms. The scope of this SBIR project is to evaluate a new class of molecules, called the 2-aminoimidazoles (2-AIs), for treating biofilm-based infections in chronic wounds. The 2-AI molecules are the first class of non- microbicidal small molecules that have been shown to disperse biofilms of both Gram-positive and Gram- negative bacteria. Given the non-microbicidal nature of the 2-AI molecules, they do not create a selective environment that could lead to the development of resistance. Over one-hundred 2-AI molecules were synthesized in Phase I and evaluated for their activity using high-throughput screening at Agile Sciences and advanced in vitro models at the Center for Biofilm Engineering (CBE) at Montana State University. Through this effort, we identified a lead molecule, named H10, which effectively disperses robust biofilms of S. aureus and P. aeruginosa formed with a drip flow reactor. Furthermore, full closure of a wound in a human keratinocyte cell scratch closure model was achieved when conditioned media from S. aureus biofilms was treated with H10. These results provide strong in vitro evidence of the potential of the 2-AI compounds to treat biofilm-based infections in chronic wounds, and motivate our Phase II project. In Phase II, we will: 1) evaluate the effectiveness of H10 in two standard in vivo wound models (rabbit ear and porcine) and 2) conduct safety evaluations in order to inform subsequent IND-enabling toxicity studies. Evaluations of H10 as a topical therapeutic using the rabbit ear wound model and the pig wound model will be performed Dr. Robert Galiano of Northwestern (rabbit model) and Dr. Stephen Davis of the University of Miami (pig model) with Dr. Garth James of the CBE providing biofilm imaging support. Since H10 is non-microbicidal, it will be co-dosed with an antibiotic to provide synergistic removal of the biofilm in addition to killing of the bacteria. Contract Research Organizations that are well-versed in drug safety will perform genotoxicity, skin irritation, cytochrome P450 inhibition, and acute toxicity evaluations. The metric of success for this Phase II project is to identify an H10-antimicrobial combination that enhances wound healing in vivo and possesses a favorable toxicity profile. The combination therapy identified in this work will be advanced to IND-enabling toxicity studies to be conducted under GLP conditions in Phase III.
