Development of a High-Throughput Screen and Its Use in the Discovery of Streptococcus pneumoniae Immunoglobulin A1 Protease Inhibitors

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• 作者：Amanda L. Garner ; Jessica L. Fullagar ; Joshua A. Day ; Seth M. Cohen ; Kim D. Janda
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：July 10, 2013
• 年：2013
• 卷：135
• 期：27
• 页码：10014-10017
• 全文大小：253K
• 年卷期：v.135,no.27(July 10, 2013)
• ISSN：1520-5126

文摘

Streptococcus pneumoniae relies on a number of virulence factors, including immunoglobulin A1 protease (IgA1P), a Zn²⁺ metalloprotease produced on the extracellular surface of the bacteria, to promote pathogenic colonization. IgA1P exhibits a unique function, in that it catalyzes the proteolysis of human IgA1 at its hinge region to leave the bacterial cell surface masked by IgA1 Fab, enabling the bacteria to evade the host鈥檚 immune system and adhere to host epithelial cells to promote colonization. Thus, S. pneumoniae IgA1P has emerged as a promising antibacterial target; however, the lack of an appropriate screening assay has limited the investigation of this metalloprotease virulence factor. Relying on electrostatics-mediated AuNP aggregation, we have designed a promising high-throughput colorimetric assay for IgA1P. By using this assay, we have uncovered inhibitors of the enzyme that should be useful in deciphering its role in pneumococcal colonization and virulence.