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3-Hydroxy-1-alkyl-2-methylpyridine-4(1H)-thiones: Inhibition of the Pseudomonas aeruginosa Virulence Factor LasB
Author(s) -
Amanda L. Garner,
Anjali K. Struss,
Jessica L. Fullagar,
Arpita Agrawal,
Amira Y. Moreno,
Seth M. Cohen,
Kim D. Janda
Publication year - 2012
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml300128f
Subject(s) - pseudomonas aeruginosa , virulence , microbiology and biotechnology , virulence factor , biofilm , swarming motility , antibiotic resistance , pyocyanin , antibiotics , staphylococcus aureus , biology , swarming (honey bee) , antimicrobial , bacteria , chemistry , quorum sensing , gene , biochemistry , genetics
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 "second generation" antibiotic approach. In Pseudomonas aeruginosa, a Zn(2+) 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 non-peptidic 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.

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