Grant: Project Grant

Antimicrobial resistance is a global health community crisis often called a "silent pandemic" as it outpaces the development of life-saving drugs. As a result, infections that were once easy to treat are becoming more difficult and sometimes impossible to cure. Escherichia coli is bacteria that naturally resides in the gut. However, if they start to invade other parts of the body, such as the bladder or kidney, they can cause serious inflections including urinary tract infections, leading to dangerous complications, especially among vulnerable populations. Central to this crisis are biofilms, bacterial communities embedded in slimy matrix where bacteria are protected from antibiotics and host immune system, allowing them to survive treatments and spread resistance. Therefore, an approach, different from conventional antibiotics is needed to combat these communities. Our research focuses on targeting bacterial structures required for building biofilms instead of killing bacteria - surface appendices, called pili and flagella, which are the main tools for E. coli to attach to human cells, invade them, and form biofilms. We discovered that assembly of pili and flagella is dependent on a bacterial protein, called GlpG. When GlpG is blocked, E. coli loses its surface appendices, becoming harmless "bald" bacteria, unable to colonize host cells. Our lab has designed powerful compounds or prototype drugs that inhibit GlpG. We have demonstrated that these compounds successfully prevent pathogenic E. coli cells from building pili and flagella. In this proposal we will improve the properties of our compounds and test their effectiveness to block bacterial ability to colonize the host cells, prevent biofilm formation and infection in lab and animal models. Ultimately, this work will advance our understanding of how bacteria cause infection and support the development of urgently needed new treatments.