title: 3-Hydroxy-1-alkyl-2-methylpyridine-4(1H)-thiones: Inhibition of the Pseudomonas aeruginosa Virulence Factor LasB.
abstract: 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.
authors.affiliation: Departments of Chemistry and Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, The Worm Institute for Research and Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, United States.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Garner
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Struss
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fullagar
authors.forename: Arpita
authors.initials: A
authors.lastname: Agrawal
authors.forename: Amira Y
authors.initials: AY
authors.lastname: Moreno
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda