Unraveling outer membrane assembly pathways… and disrupting them.
Our research projects span diverse Gram-negative pathogens. We are focused on understanding the essential steps that these bacteria rely on to build their outer membrane (OM) antibiotic barrier. By exploring this question among evolutionarily diverse pathogens, we aim to pin-point commonalities that can targeted for broad-spectrum novel antibiotics. Meanwhile, understanding how OM assembly differs among bacteria (and why these differences evolved) offers us fundamental insights into bacterial cell biology and may find opportunities for highly-selective therapeutics that treat key human pathogens but spare resident Gram-negative microbiota species.Below is an overview of our recent studies. If you are a prospective student, post-doc, or scientist and are interested in our current research program, please contact Marcin (marcin.grabowicz@emory.edu).
Lipoprotein trafficking, the key to building an outer membrane barrier
Several molecular machines have been discovered that stitch together individual lipid and protein molecules into a robust OM barrier. The Bam machine folds and inserts transmembrane proteins (termed OMPs) in the outer membrane; OMPs allow nutrients to enter the cell and also enable efflux of antibiotics out of the cell. The Lpt machine transports lipopolysaccharide (LPS) to the external surface of the OM. This layer of LPS molecules fortifies the OM.
Lipoproteins (a family of lipid-anchored proteins at the OM) are essential components in Bam, Lpt and all the OM assembly machinery. Lipoproteins are made in the inner membrane and must be trafficked to the OM. Gram-negative bacteria are critically reliant on efficient trafficking of lipoproteins in order to supply the OM assembly machines and, hence, maintain a robust antibiotic barrier. OM lipoproteins also play fundamental roles in building the cell wall, antibiotic efflux, secretion of proteins and polysaccharides, as well as contributing in diverse ways to virulence of pathogens.
We are working to develop a more complete understanding of how essential lipoproteins reach the outer membrane among diverse Gram-negative species
Envelope stress responses that monitor outer membrane assembly
OM assembly is a complex and orchestrated process that is continuously monitored by stress-responsive signal transduction systems. These systems act to preserve OM antibiotic barrier integrity when the OM is damaged during infection or during antibiotic therapy. We discovered a stress response in E. coli that monitors OM lipoprotein trafficking. We continue working to identify how important human pathogens can sense OM damage and how they attempt to repair the barrier.
We are working to identify how important human pathogens can sense OM damage and how they attempt to repair the barrier. We aim to interfere in these processes with novel inhibitors
Novel antibiotic discovery
The OM is a major hurdle for antibiotic penetration into the cell. We are working to identify and develop new inhibitors of essential OM assembly systems that will kill Gram-negative pathogens or act as adjuvants that expand the clinical usefulness of existing antibiotics against Gram-negative infections.
We aim to translate our basic science discoveries into new therapeutics that alleviate the clinical impact of antibiotic resistance