s. aureus Pore-forming toxins
Staphylococcus aureus is a Gram-positive bacterium associated with hospital- and community-acquired infections in humans. S. aureus is responsible for diverse disease states, ranging from skin infections to bacteremia, and causes thousands of deaths worldwide. Increasing antibiotic resistance (e.g. methicillin-resistant S. aureus-MRSA) and the lack of an available vaccine contributes to emergence of S. aureus as a particularly challenging pathogen.
Model of LukAB mode of action
S. aureus produces many different virulence factors, and among these are the bi-component leukocidins. This is a class of secreted toxins that have evolved to utilize receptors on innate immune cells, targeting the cells that are meant to protect us against infection. These toxins are made up of a heterodimeric complex that, upon oligomerization, undergoes a conformational change to form an octameric beta-barrel pore in the host cell membrane, leading to cell lysis. The mechanism by which these toxins form pores remains unknown. Understanding the structure-function relationship of these toxins will provide insight into how they work, and will contribute to the effort of developing anti-leukocidin therapeutics.
Negative stain EM of S. aureus toxin in complex with Fabs
In collaboration with Victor Torres, we are using X-ray crystallography, cryo-EM, and biochemical assays to determine the mechanism of this potent virulence factor.
Questions we are currently addressing include:
1. How does the structural diversity of the leukocidins modulate their tropism and potency?
2. What is the mechanism of toxin oligomerization that ultimately leads to pore insertion in the host cell membrane?