A novel bioassay to identify anti-virulence leads against gram-positive bacterial pathogens

Abstract

Infections from drug resistant bacteria result in millions of illnesses and thousands of deaths annually in the US each year, and cost an estimated $55 billion. The anti-virulence approach has emerged as a promising method for combating these infections. In theory, an anti-virulence therapeutic would reduce bacterial pathogenesis, resulting in clearance by the host without promoting resistance. Our lab has developed a novel phenotypical bioassay to identify new broad spectrum anti-virulence therapeutic leads. Utilizing a uniquely engineered strain of Staphylococcus aureus coupled to a novel mass spectrometry detection method, we have screened for compounds that interact with a very specific target within the quorum sensing system of Gram-positive bacteria, AgrB. This method has allowed us to efficiently screen over 500 natural product compounds, as well as numerous plant and fungal extracts. We have also employed the new assay to demonstrate that the fungal metabolite ambuic acid targets AgrB, and has broad-spectrum activity against multiple pathogenic bacteria.