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Biology-Based Discovery of Anti-Infectives and their Targets

Multidrug resistant (MDR) bacterial infections are increasing worldwide, and new therapies are urgently needed. Novel approaches to killing Gram-negative bacterial pathogens are especially important because small molecules are excluded by the outer membrane and efflux pumps.

Our lab is focused on identifying and characterizing new compounds that disrupt infections caused by Gram-negative bacterial pathogens. We use a tissue-culture-based screening method, called SAFIRE, to discover chemicals with anti-infective activity. We then exploit a combination of bacterial and host genetics, cell biology, biochemical, and physiological assays, in silico methods, and microscopy to determine the mechanisms of action of these anti-infectives and to discover their cellular and molecular targets. Our long-term goal is to uncover new therapeutic approaches against MDR bacteria.

The kinds of anti-infective molecules we are pursuing include the following:

Efflux Pump Inhibitors – Like all cells, bacteria need to export waste and toxic molecules, including antibiotics. Small molecules that bind to bacterial efflux pumps and slow or prevent the export of other substrates have the potential to become useful anti-infectives, especially in combination with existing clinical antibiotics. We are pursuing projects on efflux pump inhibitors in the lab and with a small biotech company, .

Compounds that synergize with host innate immunity – Gram-negative bacteria have an inner, cell membrane that is protected by a combination of the outer membrane and efflux pumps. During infection, host soluble innate immunity permeabilizes the outer membrane and produces anti-bacterial compounds that occupy efflux pumps. We have identified small molecules that appear to exploit these aspects of host innate immunity to stop infection. We are exploring how these anti-infectives act and how they synergize with host innate immunity.