Nearly 11,000 people died last year alone from a methicillin-resistant Staphylococcus aureus (MRSA)-related infection in the United States; this figure represents nearly half of all fatalities caused by antibiotic-resistant bacteria. It is well established that currently approved antimicrobials are losing the battle in the fight against multidrug-resistant pathogens. Without a doubt, novel antimicrobials and novel approaches to develop them are urgently needed; however, new antimicrobials are becoming increasingly difficult to develop. Repurposing FDA-approved drugs, with well-characterized toxicology and pharmacology, to find new applications outside the scope of the original medical indication is a novel way to reduce both the time and cost associated with antimicrobial innovation. Studies proposed in this application build upon discoveries of the potent bactericidal activity of the non- antimicrobial drugs auranofin, ebselen and FdUrd, in an applicable clinical range, against highly multidrug- resistant Gram-positive pathogens, including MRSA. Our preliminary studies strongly suggest that repurposing these drugs as an antimicrobial agent to treat MRSA infections will leapfrog the drug development process and save years of expensive research. The fact that auranofin recently has been granted orphan-drug status from the FDA for treatment of human amebiasis, further validates our approach. The goal of this application is to further develop, optimize, and validate auranofin, ebselen, and FdUrd as potential treatment for MRSA infections. In addition, we will evaluate the therapeutic efficacy of these drugs in a mouse wound-model that closely approximates the condition of diabetic foot ulcers in humans; this is expected to advance current knowledge in chronic wound care. Our findings in MRSA will be broadly relevant to other important pathogens impacting global public health. Furthermore, our work to repurpose these drugs should significantly impact and inform efforts by other researchers to repurpose other therapeutic agents as visible treatment options for multidrug-resistant pathogens.
Staphylococcus aureus infections have become a serious threat to the global public health due to the dearth of effective antimicrobials. There is no doubt that there is a critical unmet need for a novel antibacterial agent to treat these infections. The proposed research is expected to have a significant positive impact on human health by validating the non-antimicrobial FDA approved drugs as antimicrobial agents, which may lead to the development of a new class of antimicrobial drug that can be used to treat infections caused by highly resistant pathogens.
