Synthesis and biological evaluation of reversible inhibitors of IdeS, a bacterial cysteine protease and virulence determinant

Berggren, Kristina; Johansson, Börje; Fex, Tomas; Kihlberg, Jan; Björck, Lars; Luthman, Kristina

doi:10.1016/j.bmc.2009.03.026

Cited by 6 publications

(7 citation statements)

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“…The streptococcal mitogenic exotoxin Z (SmeZ) is the most potent bacterial superantigen so far discovered and enhances the cascade of pro-inflammatory events that follow invasive streptococcal infection [29], [30]. GAS also secretes a highly effective IgG endopeptidase (IdeS) that inhibits phagocytic killing by cleavage of specific IgG [31], [32], [33]. Finally, though not listed in the top 15 up- and downregulated GAS serotype M3 MGAS16655 genes, the virulence factors streptolysin O (SLO) and streptolysin S (SLS) showed significant differences in expression during co-culture.…”

Section: Discussionmentioning

confidence: 99%

Differential Virulence Gene Expression of Group A Streptococcus Serotype M3 in Response to Co-Culture with Moraxella catarrhalis

et al. 2013

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Streptococcus pyogenes (group A Streptococcus, GAS) and Moraxella catarrhalis are important colonizers and (opportunistic) pathogens of the human respiratory tract. However, current knowledge regarding colonization and pathogenic potential of these two pathogens is based on work involving single bacterial species, even though the interplay between respiratory bacterial species is increasingly important in niche occupation and the development of disease. Therefore, to further define and understand polymicrobial species interactions, we investigated whether gene expression (and hence virulence potential) of GAS would be affected upon co-culture with M. catarrhalis. For co-culture experiments, GAS and M. catarrhalis were cultured in Todd-Hewitt broth supplemented with 0.2% yeast extract (THY) at 37°C with 5% CO2 aeration. Each strain was grown in triplicate so that triplicate experiments could be performed. Bacterial RNA was isolated, cDNA synthesized, and microarray transcriptome expression analysis performed. We observed significantly increased (≥4-fold) expression for genes playing a role in GAS virulence such as hyaluronan synthase (hasA), streptococcal mitogenic exotoxin Z (smeZ) and IgG endopeptidase (ideS). In contrast, significantly decreased (≥4-fold) expression was observed in genes involved in energy metabolism and in 12 conserved GAS two-component regulatory systems. This study provides the first evidence that M. catarrhalis increases GAS virulence gene expression during co-culture, and again shows the importance of polymicrobial infections in directing bacterial virulence.

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Section: Discussionmentioning

confidence: 99%

Differential Virulence Gene Expression of Group A Streptococcus Serotype M3 in Response to Co-Culture with Moraxella catarrhalis

et al. 2013

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“…So far, two studies addressed the identification of specific inhibitors to IdeS. One employed analogs to the well-known serine protease inhibitors TPCK (tosyl phenylalanyl chloromethyl ketone) and TLCK (tosyl lysyl chloromethyl ketone) to demonstrate the reversible inhibition of IdeS by replacing the active α-chloro-ketone by aldehyde [55]. In another study, peptide analogs based on the P 4 -P′ 4 residues of IgG and carrying a piperidine moiety in one of the two glycine residues of the cleavage site were investigated for their inhibitory activity on IdeS [56], with several being found to have significant inhibitory capacity independently of N -terminal or C -terminal amino acid extensions [56].…”

Section: Counteracting Ides Activitymentioning

confidence: 99%

Streptococcal IdeS and Its Impact on Immune Response and Inflammation

Pawel‐Rammingen¹

2012

J Innate Immun

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Survival of the important bacterial pathogen Streptococcus pyogenes relies on its ability to circumvent the antimicrobial actions of innate and specific immune responses and to modulate the inflammatory responses induced during the course of an infection. Inflammatory processes play key roles during streptococcal pathogenesis and streptococcal infections are accompanied by an intense inflammatory state. As an exclusively human pathogen, S. pyogenes has adapted to the various countermeasures employed by its host to fight bacterial infections, in particular to interfere with the effector functions of immunoglobulin G (IgG). For this purpose, S. pyogenes has evolved an IgG-specific endopeptidase, IdeS, which is highly specific for the lower hinge region of IgG. This review summarizes the current knowledge about this intriguing enzyme as well as its role in inflammation and in the attenuation of human immune responses towards streptococcal infection.

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“…Its 1 H NMR spectrum lacked the triplet and quartet signals assigned for CH 3 CH 2 protons of its precursor and showed two new D 2 Oexchangeable signals for hydrazide NH 2 and hydrazide NH protons, in addition to the usual signals at their expected chemical shifts. Treating 6 with benzene or toluenesulfonyl chloride in dry pyridine, in accordance to the previously described procedures, 20,21 afforded N-ĳ(2-aminobenzothiazol-6-yloxy)methylcarbonyl]arylsulfohydrazides 7 and 8. Upon carbamoylation with methyl chloroformate in pyridine as reported, 19 they produced corresponding carbamates 9 and 10.…”

Section: Chemistrymentioning

confidence: 99%

“…IR ν (KBr, cm −1 ): 3177 (NH), 1759, 1722 (2 × CO), 1608 (CN), 1583, 1470 (CC Ar), 1251, 1098 (ν as and ν s C-O-C). MS m/z (%): 310 (54), 279 (24), 278 (85), 251 (20), 237 (14), 223 (46), 206 (9), 192 (25), 191 (100), 179 (26), 165 (80), 164 (56), 150 (19), 134 (12) (7,8). A stirred solution of 6 (0.…”

Section: Chemistrymentioning

confidence: 99%

Design, facile synthesis and anthelmintic activity of new O-substituted 6-methoxybenzothiazole-2-carbamates

et al. 2015

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Synthesis and biological evaluation of reversible inhibitors of IdeS, a bacterial cysteine protease and virulence determinant

Cited by 6 publications

References 36 publications

Differential Virulence Gene Expression of Group A Streptococcus Serotype M3 in Response to Co-Culture with Moraxella catarrhalis

Differential Virulence Gene Expression of Group A Streptococcus Serotype M3 in Response to Co-Culture with Moraxella catarrhalis

Streptococcal IdeS and Its Impact on Immune Response and Inflammation

Design, facile synthesis and anthelmintic activity of new O-substituted 6-methoxybenzothiazole-2-carbamates

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