Jing Dong, Jiazhang Qiu, Yu Zhang, Chongjian Lu, Xiaohan Dai, Jianfeng Wang, Hongen Li, Xin Wang, Wei Tan, Mingjing Luo, Xiaodi Niu, Xuming Deng
PLoS computational biology 2013Alpha-hemolysin (α-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, α-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 α-HL. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were performed to understand the formation of the α-HL-ORO complex. This combined approach revealed that the catalytic mechanism of inhibition involves the direct binding of ORO to α-HL, which blocks the conformational transition of the critical "Loop" region of the α-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 α-HL-mediated injury. These findings indicate that ORO hinders the lytic activity of α-HL through a novel mechanism, which should facilitate the design of new and more effective antibacterial agents against S. aureus.
Jing Dong, Jiazhang Qiu, Yu Zhang, Chongjian Lu, Xiaohan Dai, Jianfeng Wang, Hongen Li, Xin Wang, Wei Tan, Mingjing Luo, Xiaodi Niu, Xuming Deng. Oroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore. PLoS computational biology. 2013;9(1):e1002869
PMID: 23349625
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