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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Nov 28

PMID 23181168

Citations 19

Authors

Amanda L Garner

Anjali K Struss

Jessica L Fullagar

Arpita Agrawal

Amira Y Moreno

Seth M Cohen

Kim D Janda

Affiliations

Soon will be listed here.

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.

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References

Wu H, Lee B, Yang L, Wang H, Givskov M, Molin S . Effects of ginseng on Pseudomonas aeruginosa motility and biofilm formation. FEMS Immunol Med Microbiol. 2011; 62(1):49-56. DOI: 10.1111/j.1574-695X.2011.00787.x. View

Overhage J, Bains M, Brazas M, Hancock R . Swarming of Pseudomonas aeruginosa is a complex adaptation leading to increased production of virulence factors and antibiotic resistance. J Bacteriol. 2008; 190(8):2671-9. PMC: 2293252. DOI: 10.1128/JB.01659-07. View

Flipo M, Charton J, Hocine A, Dassonneville S, Deprez B, Deprez-Poulain R . Hydroxamates: relationships between structure and plasma stability. J Med Chem. 2009; 52(21):6790-802. DOI: 10.1021/jm900648x. View

Mesaros N, Nordmann P, Plesiat P, Roussel-Delvallez M, Van Eldere J, Glupczynski Y . Pseudomonas aeruginosa: resistance and therapeutic options at the turn of the new millennium. Clin Microbiol Infect. 2007; 13(6):560-78. DOI: 10.1111/j.1469-0691.2007.01681.x. View

Stowe G, Silhar P, Hixon M, Silvaggi N, Allen K, Moe S . Chirality holds the key for potent inhibition of the botulinum neurotoxin serotype a protease. Org Lett. 2010; 12(4):756-9. PMC: 2821465. DOI: 10.1021/ol902820z. View

capkova K, Salzameda N, Janda K . Investigations into small molecule non-peptidic inhibitors of the botulinum neurotoxins. Toxicon. 2009; 54(5):575-82. PMC: 2730986. DOI: 10.1016/j.toxicon.2009.03.016. View

Agrawal A, Johnson S, Jacobsen J, Miller M, Chen L, Pellecchia M . Chelator fragment libraries for targeting metalloproteinases. ChemMedChem. 2010; 5(2):195-9. PMC: 2825879. DOI: 10.1002/cmdc.200900516. View

Agrawal A, de Oliveira C, Cheng Y, Jacobsen J, McCammon J, Cohen S . Thioamide hydroxypyrothiones supersede amide hydroxypyrothiones in potency against anthrax lethal factor. J Med Chem. 2009; 52(4):1063-74. PMC: 2698031. DOI: 10.1021/jm8013212. View

Nishino N, POWERS J . Pseudomonas aeruginosa elastase. Development of a new substrate, inhibitors, and an affinity ligand. J Biol Chem. 1980; 255(8):3482-6. View

10.

Boldt G, Kennedy J, Janda K . Identification of a potent botulinum neurotoxin a protease inhibitor using in situ lead identification chemistry. Org Lett. 2006; 8(8):1729-32. PMC: 2733786. DOI: 10.1021/ol0603211. View

11.

Pearson J, Gray K, Passador L, Tucker K, Eberhard A, Iglewski B . Structure of the autoinducer required for expression of Pseudomonas aeruginosa virulence genes. Proc Natl Acad Sci U S A. 1994; 91(1):197-201. PMC: 42913. DOI: 10.1073/pnas.91.1.197. View

12.

Cathcart G, Gilmore B, Greer B, Harriott P, Walker B . Inhibitor profiling of the Pseudomonas aeruginosa virulence factor LasB using N-alpha mercaptoamide template-based inhibitors. Bioorg Med Chem Lett. 2009; 19(21):6230-2. DOI: 10.1016/j.bmcl.2009.08.099. View

13.

Puerta D, Griffin M, Lewis J, Romero-Perez D, Garcia R, Villarreal F . Heterocyclic zinc-binding groups for use in next-generation matrix metalloproteinase inhibitors: potency, toxicity, and reactivity. J Biol Inorg Chem. 2006; 11(2):131-8. DOI: 10.1007/s00775-005-0053-x. View

14.

Cathcart G, Quinn D, Greer B, Harriott P, Lynas J, Gilmore B . Novel inhibitors of the Pseudomonas aeruginosa virulence factor LasB: a potential therapeutic approach for the attenuation of virulence mechanisms in pseudomonal infection. Antimicrob Agents Chemother. 2011; 55(6):2670-8. PMC: 3101427. DOI: 10.1128/AAC.00776-10. View

15.

Woods D, Cryz S, Friedman R, Iglewski B . Contribution of toxin A and elastase to virulence of Pseudomonas aeruginosa in chronic lung infections of rats. Infect Immun. 1982; 36(3):1223-8. PMC: 551460. DOI: 10.1128/iai.36.3.1223-1228.1982. View

16.

capkova K, Yoneda Y, Dickerson T, Janda K . Synthesis and structure-activity relationships of second-generation hydroxamate botulinum neurotoxin A protease inhibitors. Bioorg Med Chem Lett. 2007; 17(23):6463-6. PMC: 2170532. DOI: 10.1016/j.bmcl.2007.09.103. View

17.

Kessler E, Israel M, Landshman N, Chechick A, Blumberg S . In vitro inhibition of Pseudomonas aeruginosa elastase by metal-chelating peptide derivatives. Infect Immun. 1982; 38(2):716-23. PMC: 347797. DOI: 10.1128/iai.38.2.716-723.1982. View

18.

Jacobsen F, Buczynski M, Dennis E, Cohen S . A macrophage cell model for selective metalloproteinase inhibitor design. Chembiochem. 2008; 9(13):2087-95. PMC: 2826882. DOI: 10.1002/cbic.200800148. View

19.

Barczak A, Hung D . Productive steps toward an antimicrobial targeting virulence. Curr Opin Microbiol. 2009; 12(5):490-6. PMC: 2763366. DOI: 10.1016/j.mib.2009.06.012. View

20.

Kamath S, Kapatral V, Chakrabarty A . Cellular function of elastase in Pseudomonas aeruginosa: role in the cleavage of nucleoside diphosphate kinase and in alginate synthesis. Mol Microbiol. 1999; 30(5):933-41. DOI: 10.1046/j.1365-2958.1998.01121.x. View