Project Team

• Garth D. Ehrlich, PhD, Professor of Microbiology & Immunology
• Hai-Feng (Frank) JI, PhD, Professor of Chemistry

Abstract

Background

Bacterial biofilms form when free-swimming bacteria transition from a single-celled lifestyle to multicellular organisms. These multicellular biofilms are responsible for 80% or more of chronic bacterial infections. Unfortunately, biofilms are recalcitrant to treatment with all standard antibiotics. This results from the formation of persister cells in the biofilm that have triggered an ancient and highly conserved type of starvation metabolism termed the stringent response that functions to turn them into the bacterial equivalent of stem cells. Stem cells and persisters are different than other cells in that they adjust their metabolism for long term survival as opposed to rapid metabolism and division. They do this by up-regulating their ability to deal with oxidative stress. It is this ability that provides for their phenomenal resistance to antibiotics – as all classes of antibiotics kill through the production of reactive oxygen species.

Aim

To develop and test a small molecule inhibitor of the bacterial RelA enzyme which triggers the stringent response through the production of the “alarmone” ppGpp (also called magic spot) to re- potentiate all antibiotics against biofilm bacteria.

Preliminary Results

We have identified two classes of small molecules that bind within the active site more strongly than the natural ligand GTP. These molecules pass Lapiniski’s rule of five for druggability and have been demonstrated in vitro to both potentiate killing of multiple species of bacterial biofilms by antibiotics and to affect the structure of the biofilm.