Journal
PLOS COMPUTATIONAL BIOLOGY
Volume 9, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1002869
Keywords
-
Funding
- National Basic Research Program of China [2013CB127205]
- Jilin University [2012JC022]
Ask authors/readers for more resources
Alpha-hemolysin (alpha-HL) is a self-assembling, channel-forming toxin produced by most Staphylococcus aureus strains as a 33.2-kDa soluble monomer. Upon binding to a susceptible cell membrane, the monomer self-assembles to form a 232.4-kDa heptamer that ultimately causes host cell lysis and death. Consequently, alpha-HL plays a significant role in the pathogenesis of S. aureus infections, such as pneumonia, mastitis, keratitis and arthritis. In this paper, experimental studies show that oroxylin A (ORO), a natural compound without anti-S. aureus activity, can inhibit the hemolytic activity of alpha-HL. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were performed to understand the formation of the alpha-HL-ORO complex. This combined approach revealed that the catalytic mechanism of inhibition involves the direct binding of ORO to alpha-HL, which blocks the conformational transition of the critical Loop'' region of the alpha-HL protein thereby inhibiting its hemolytic activity. This mechanism was confirmed by experimental data obtained from a deoxycholate-induced oligomerization assay. It was also found that, in a co-culture system with S. aureus and human alveolar epithelial (A549) cells, ORO could protect against alpha-HL-mediated injury. These findings indicate that ORO hinders the lytic activity of alpha-HL through a novel mechanism, which should facilitate the design of new and more effective antibacterial agents against S. aureus.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available