Identification of Bacterial Target Proteins for the Salicylidene Acylhydrazide Class of Virulence-blocking Compounds

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Jul 5

PMID 21724850

Citations 48

Authors

Dai Wang

Caroline E Zetterstrom

Mads Gabrielsen

Katherine S H Beckham

Jai J Tree

Sarah E Macdonald

Olwyn Byron

Tim J Mitchell

David L Gally

Pawel Herzyk

Arvind Mahajan

Hanna Uvell

Richard Burchmore

Brian O Smith

Mikael Elofsson

Andrew J Roe

Affiliations

Soon will be listed here.

Abstract

A class of anti-virulence compounds, the salicylidene acylhydrazides, has been widely reported to block the function of the type three secretion system of several Gram-negative pathogens by a previously unknown mechanism. In this work we provide the first identification of bacterial proteins that are targeted by this group of compounds. We provide evidence that their mode of action is likely to result from a synergistic effect arising from a perturbation of the function of several conserved proteins. We also examine the contribution of selected target proteins to the pathogenicity of Yersinia pseudotuberculosis and to expression of virulence genes in Escherichia coli O157.

Citing Articles

Targeting bacterial pathogenesis by inhibiting virulence-associated Type III and Type IV secretion systems.

Blasey N, Rehrmann D, Riebisch A, Muhlen S Front Cell Infect Microbiol. 2023; 12:1065561.

PMID: 36704108 PMC: 9872159. DOI: 10.3389/fcimb.2022.1065561.

Effects of the Quinone Oxidoreductase WrbA on Biofilm Formation and Oxidative Stress.

Rossi F, Catto C, Mugnai G, Villa F, Forlani F Antioxidants (Basel). 2021; 10(6).

PMID: 34204135 PMC: 8229589. DOI: 10.3390/antiox10060919.

Developing Cyclic Peptomers as Broad-Spectrum Type III Secretion System Inhibitors in Gram-Negative Bacteria.

Lam H, Lau T, Lentz A, Sherry J, Cabrera-Cortez A, Hug K Antimicrob Agents Chemother. 2021; 65(7):e0169020.

PMID: 33875435 PMC: 8373237. DOI: 10.1128/AAC.01690-20.

The Type III Secretion System: An Overview from Top to Bottom.

Muthuramalingam M, Whittier S, Picking W, Picking W Microorganisms. 2021; 9(2).

PMID: 33671545 PMC: 7926512. DOI: 10.3390/microorganisms9020451.

Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components.

Hotinger J, Pendergrass H, May A Biomolecules. 2021; 11(2).

PMID: 33669653 PMC: 7922566. DOI: 10.3390/biom11020316.

References

Horst S, Jaeger T, Denkel L, Rouf S, Rhen M, Bange F . Thiol peroxidase protects Salmonella enterica from hydrogen peroxide stress in vitro and facilitates intracellular growth. J Bacteriol. 2010; 192(11):2929-32. PMC: 2876503. DOI: 10.1128/JB.01652-09. View

Guiffant D, Tribouillard D, Gug F, Galons H, Meijer L, Blondel M . Identification of intracellular targets of small molecular weight chemical compounds using affinity chromatography. Biotechnol J. 2007; 2(1):68-75. DOI: 10.1002/biot.200600223. View

Kauppi A, Andersson C, Norberg H, Sundin C, Linusson A, Elofsson M . Inhibitors of type III secretion in Yersinia: design, synthesis and multivariate QSAR of 2-arylsulfonylamino-benzanilides. Bioorg Med Chem. 2007; 15(22):6994-7011. DOI: 10.1016/j.bmc.2007.07.047. View

Chu H, Slepenkin A, Elofsson M, Keyser P, de la Maza L, Peterson E . Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseriagonorrhoeae. Int J Antimicrob Agents. 2010; 36(2):145-50. PMC: 2902681. DOI: 10.1016/j.ijantimicag.2010.03.018. View

Leslie B, Hergenrother P . Identification of the cellular targets of bioactive small organic molecules using affinity reagents. Chem Soc Rev. 2008; 37(7):1347-60. DOI: 10.1039/b702942j. View

Simmons K, Chopra I, Fishwick C . Structure-based discovery of antibacterial drugs. Nat Rev Microbiol. 2010; 8(7):501-10. DOI: 10.1038/nrmicro2349. View

Bailey L, Gylfe A, Sundin C, Muschiol S, Elofsson M, Nordstrom P . Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle. FEBS Lett. 2007; 581(4):587-95. DOI: 10.1016/j.febslet.2007.01.013. View

Coburn B, Sekirov I, Finlay B . Type III secretion systems and disease. Clin Microbiol Rev. 2007; 20(4):535-49. PMC: 2176049. DOI: 10.1128/CMR.00013-07. View

Wolf K, Betts H, Chellas-Gery B, Hower S, Linton C, Fields K . Treatment of Chlamydia trachomatis with a small molecule inhibitor of the Yersinia type III secretion system disrupts progression of the chlamydial developmental cycle. Mol Microbiol. 2006; 61(6):1543-55. PMC: 1615999. DOI: 10.1111/j.1365-2958.2006.05347.x. View

10.

Vranken W, Boucher W, Stevens T, Fogh R, Pajon A, Llinas M . The CCPN data model for NMR spectroscopy: development of a software pipeline. Proteins. 2005; 59(4):687-96. DOI: 10.1002/prot.20449. View

11.

Nachin L, Nannmark U, Nystrom T . Differential roles of the universal stress proteins of Escherichia coli in oxidative stress resistance, adhesion, and motility. J Bacteriol. 2005; 187(18):6265-72. PMC: 1236625. DOI: 10.1128/JB.187.18.6265-6272.2005. View

12.

Schuck P . Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and lamm equation modeling. Biophys J. 2000; 78(3):1606-19. PMC: 1300758. DOI: 10.1016/S0006-3495(00)76713-0. View

13.

Rietsch A, Mekalanos J . Metabolic regulation of type III secretion gene expression in Pseudomonas aeruginosa. Mol Microbiol. 2006; 59(3):807-20. PMC: 2654213. DOI: 10.1111/j.1365-2958.2005.04990.x. View

14.

Hudson D, Layton A, Field T, Bowen A, Wolf-Watz H, Elofsson M . Inhibition of type III secretion in Salmonella enterica serovar Typhimurium by small-molecule inhibitors. Antimicrob Agents Chemother. 2007; 51(7):2631-5. PMC: 1913257. DOI: 10.1128/AAC.01492-06. View

15.

Morphy R, Rankovic Z . Designing multiple ligands - medicinal chemistry strategies and challenges. Curr Pharm Des. 2009; 15(6):587-600. DOI: 10.2174/138161209787315594. View

16.

Muschiol S, Bailey L, Gylfe A, Sundin C, Hultenby K, Bergstrom S . A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis. Proc Natl Acad Sci U S A. 2006; 103(39):14566-71. PMC: 1566191. DOI: 10.1073/pnas.0606412103. View

17.

Baron C . Antivirulence drugs to target bacterial secretion systems. Curr Opin Microbiol. 2010; 13(1):100-5. DOI: 10.1016/j.mib.2009.12.003. View

18.

Payne D, Gwynn M, Holmes D, Pompliano D . Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2006; 6(1):29-40. DOI: 10.1038/nrd2201. View

19.

Ploom T, Haussmann C, Hof P, Steinbacher S, Bacher A, Richardson J . Crystal structure of 7,8-dihydroneopterin triphosphate epimerase. Structure. 1999; 7(5):509-16. DOI: 10.1016/s0969-2126(99)80067-7. View

20.

Dahlgren M, Zetterstrom C, Gylfe S, Linusson A, Elofsson M . Statistical molecular design of a focused salicylidene acylhydrazide library and multivariate QSAR of inhibition of type III secretion in the Gram-negative bacterium Yersinia. Bioorg Med Chem. 2010; 18(7):2686-703. DOI: 10.1016/j.bmc.2010.02.022. View