Targeting Bacterial Virulence

Kauppi, Anna M.; Nordfelth, Roland; Uvell, Hanna; Wolf‐Watz, Hans; Elofsson, Mikael

doi:10.1016/s1074-5521(03)00046-2

Cited by 201 publications

(111 citation statements)

References 33 publications

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“…A class of acylated hydrazones was recently identified that inhibited TTS of Y. pseudotuberculosis without affecting the in vitro growth rate (2,3). The same class of compounds has also been shown to inhibit TTS of Pseudomonas aeruginosa as well as S. typhimurium (unpublished data), suggesting that these compounds target the secretory apparatus itself rather than individual effector molecules.…”

Section: Discussionmentioning

confidence: 95%

A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis

Muschiol

Bailey²,

Gylfe³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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174

155

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The intracellular pathogen Chlamydia trachomatis possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of Yersinia pseudotuberculosis. Here, we show that one of these compounds, INP0400, inhibits intracellular replication and infectivity of C. trachomatis at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs).

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Section: Discussionmentioning

confidence: 95%

A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis

Muschiol

Bailey²,

Gylfe³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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174

155

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“…In summary, small-molecule screening provides a powerful approach to studying invasion and other experimentally challenging questions in host-pathogen interaction (2,34,35). At the same time, the approach may generate small-molecule probes that will prove useful in other experimental systems, and it may identify protein-small molecule pairs of relevance to antimicrobial drug development.…”

Section: )mentioning

confidence: 99%

A small-molecule approach to studying invasive mechanisms of Toxoplasma gondii

Carey

Westwood

Mitchison

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

128

163

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Toxoplasma gondii is the most common protozoan parasite of humans. Infection with T. gondii can lead to life-threatening disease as a result of repeated cycles of host cell invasion, parasite replication, and host cell lysis. Relatively little is known about the invasive mechanisms of T. gondii and related parasites within the Phylum Apicomplexa (including Plasmodium spp., the causative agents of malaria), due to difficulties associated with studying genes essential to invasion in haploid obligate intracellular organisms. To circumvent this problem, we have developed a highthroughput microscope-based assay, which we have used to screen a collection of 12,160 structurally diverse small molecules for inhibitors of T. gondii invasion. A total of 24 noncytotoxic invasion inhibitors were identified. Secondary assays demonstrated that different inhibitors perturb different aspects of invasion, including gliding motility, secretion of host cell adhesins from apical organelles (the micronemes), and extension of a unique tubulinbased structure at the anterior of the parasite (the conoid). Unexpectedly, the screen also identified six small molecules that dramatically enhance invasion, gliding motility, and microneme secretion. The small molecules identified here reveal a previously unrecognized complexity in the control of parasite motility and microneme secretion, and they constitute a set of useful probes for dissecting the invasive mechanisms of T. gondii and related parasites. Small-molecule-based approaches provide a powerful means to address experimentally challenging problems in host-pathogen interaction, while simultaneously identifying new potential targets for drug development. N early one-third of all deaths in the world today are caused by infectious disease. The development of new preventative and therapeutic strategies relies on an improved understanding of the interaction between pathogens and their hosts. In many pathogenic systems, this presents a formidable experimental challenge, because standard genetic tools are either rudimentary or unavailable. Biochemical, genomic, and other approaches exist, but these lack the assumption-free power of a genetic screen.An alternative nongenetic approach to studying mechanisms of host-pathogen interaction involves screening large structurally diverse collections of small molecules for those that disrupt the interaction. Once identified, the small molecules (or their derivatives) are used to determine the cellular components that function in the process (reviewed in refs. 1-3). The approach relies on the demonstrated ability of many small molecules to interact specifically with their targets (e.g., ref. 4). As with classical forward genetic screens, the approach is assumptionfree: by sampling large unbiased collections of structurally diverse small molecules, the screen ''selects'' structures that perturb the process under study. Such phenotype-based highthroughput screening has recently gained momentum in the academic setting due to technological advances and the av...

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“…A primary assay utilizing the bacterial clone Y. pseudotuberculosis YPIII(pIB102-Elux), 15 with a luminescent reporter gene under the control of the promoter for the T3SS effector protein YopE, detected three library fractions derived from both leaf extracts of two Papua New Guinean Anisoptera (Dipterocarpaceae) species, A. thurifera and A. polyandra, that inhibited the luminescent signal. To verify the positive hits a colorimetric assay to detect the protein tyrosine phosphatase enzyme activity of the secreted effector protein YopH was performed in conjunction with a standard antibacterial growth assay, 41 and suggested that these fractions selectively inhibited the T3SS.…”

Section: Resultsmentioning

confidence: 99%

“…Ca 2+ depletion at 37 °C stimulates Yop production and the Yop production will eventually suppresses growth. 15 Fractions were tested at single point concentrations of 7.14 μge/μL Active fractions and controls were retested at 7.14, 1.42, 0.71, 0.14 and 0.071 μge/μL. Pure compounds were screened at 10, 20, 50 and 100 μM.…”

Section: Acid Hydrolysis Ofmentioning

confidence: 99%

“…14 These Yops are essential for virulence and synthetic small molecules that inhibit Yop secretion have been identified. 15,16 It has been shown that the salicylidene acylhydrazide class of inhibitors can attenuate virulence without affecting bacterial growth in a number of bacterial species. [17][18][19][20][21][22][23] Several studies suggest that one of the key advantages of using virulence systems as targets for novel anti-infectives is a low probability for development of resistance.…”

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confidence: 99%

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Solving the Supply of Resveratrol Tetramers from Papua New Guinean Rainforest Anisoptera Species That Inhibit Bacterial Type III Secretion Systems

Davis

Beattie

et al. 2014

J. Nat. Prod.

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The supply of (−)-hopeaphenol (1) was achieved via enzymatic biotransformation in order to provide material for preclinical investigation. High-throughput screening of a prefractionated natural product library aimed to identify compounds that inhibit the bacterial virulence type III secretion system (T3SS) identified several fractions derived from two Papua New Guinean Anisoptera species, showing activity against Yersinia pseudotuberculosis outer proteins E and H (YopE and YopH). Bioassay-directed isolation from the leaves of A. thurifera, and similarly A. polyandra, resulted in three known resveratrol tetramers, (−)-hopeaphenol (1), vatalbinoside A (2), and vaticanol B (3). Compounds 1−3 displayed IC 50 values of 8.8, 12.5, and 9.9 μM in a luminescent reporter-gene assay (YopE) and IC 50 values of 2.9, 4.5, and 3.3 μM in an enzyme-based YopH assay, respectively, which suggested that they could potentially act against the T3SS in Yersinia. The structures of 1−3 were confirmed through a combination of spectrometric, chemical methods, and single-crystal X-ray structure determinations of the natural product 1 and the permethyl ether analogue of 3. The enzymatic hydrolysis of the β-glycoside 2 to the aglycone 1 was achieved through biotransformation using the endogenous leaf enzymes. This significantly enhanced the yield of the target bioactive natural product from 0.08% to 1.3% and facilitates ADMET studies of (−)-hopeaphenol (1).

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Targeting Bacterial Virulence

Cited by 201 publications

References 33 publications

A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis

A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis

A small-molecule approach to studying invasive mechanisms of Toxoplasma gondii

Solving the Supply of Resveratrol Tetramers from Papua New Guinean Rainforest Anisoptera Species That Inhibit Bacterial Type III Secretion Systems

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