Development of Single Agent Antibiofilm Antibiotics

Project Summary Natural products have served as a productive source of drugs over the past decades and have represented, or been the inspiration for, a majority of antimicrobial compounds that have entered the clinic. The goal of this proposal is to develop novel antibacterial agents based on the marine natural product lipoxazolidinone A to treat recalcitrant Gram-positive infections. These scaffolds have the potential to clear biofilm-implicated recalcitrant infections, including persistent tissue infections such as chronic wound infections, chronic osteomyelitis, chronic rhinosinusitis and endocarditis. These biofilm-implicated infections are tolerant to traditional antibiotics and represent a significant clinical need since up to 80% of human infections involve biofilm- associated microorganisms. Few small molecules have been isolated that have the potential to not only disrupt biofilms, but also act as an antibiotic – thereby functioning to clear biofilm associated infections. We believe there are significant advantages to a single agent treatment over an adjuvant therapy for the treatment of these slow-growing, antimicrobial tolerant infections. Herein, we propose to develop a class of compounds that is capable to addressing the treatment of biofilm associated infections and generate the key data necessary for a go/no-go decision to advance these molecules toward a Phase II pre-clinical study.Project Narrative This proposal aims to develop novel therapeutics for the treatment of recalcitrant Gram-positive bacterial infections. Specifically, this work will enable key data to focus and direct the commercialization of the 4-oxazolidinone family of natural products, molecules that have displayed unusual activity against bacterial biofilms and persister cells. The results obtained from these studies are essential for identifying a lead compound for future preclinical studies and an Investigational New Drug (IND) application.