3-Hydroxy-1-alkyl-2-methylpyridine-4(1H)-thiones: Inhibition of the Pseudomonas aeruginosa Virulence Factor LasB

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• 作者：Amanda L. Garner ; Anjali K. Struss ; Jessica L. Fullagar ; Arpita Agrawal ; Amira Y. Moreno ; Seth M. Cohen ; Kim D. Janda
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：3
• 期：8
• 页码：668-672
• 全文大小：247K
• 年卷期：v.3,no.8(August 9, 2012)
• ISSN：1948-5875

文摘

Bacterial resistance coupled to our current arsenal of antibiotics presents us with a growing threat to public health, thus warranting the exploration of alternative antibacterial strategies. In particular, the targeting of virulence factors has been regarded as a 鈥渟econd generation鈥?antibiotic approach. In Pseudomonas aeruginosa, a Zn²⁺ metalloprotease virulence factor, LasB or P. aeruginosa elastase, has been implicated in the development of P. aeruginosa-related keratitis, pneumonia, and burn infection. Moreover, the enzyme also plays a critical role in swarming and biofilm formation, both of which are processes that have been linked to antibiotic resistance. To further validate the importance of LasB in P. aeruginosa infection, we describe our efforts toward the discovery of nonpeptidic small molecule inhibitors of LasB. Using identified compounds, we have confirmed the role that LasB plays in P. aeruginosa swarming and demonstrate the potential for LasB-targeted small molecules in studying antimicrobial-resistant P. aeruginosa phenotypes.

Keywords:

antibiotics; lloprotease+inhibitors&qsSearchArea=searchText">metalloprotease inhibitors; lence+factors&qsSearchArea=searchText">virulence factors; hydroxypyridinthiones