Because of its essential role as a bacterial virulence factor, enzyme sortase A (SrtA) has become an attractive target for the development of new antivirulence drugs against Gram-positive infections. Here we describe 27 compounds identified as covalent inhibitors of Staphylococcus aureus SrtA by screening a library of approximately 50 000 compounds using a FRET assay followed by NMR-based validation and binding reversibility analysis. Nineteen of these compounds displayed only moderate to weak cytotoxicity, with CC 50 against NIH 3T3 mice fibroblast cells ranging from 12 to 740 μM. Analysis using covalent docking suggests that the inhibitors initially associate via hydrophobic interactions, followed by covalent bond formation between the SrtA active site cysteine and an electrophilic center of the inhibitor. The compounds represent good starting points that have the potential to be developed into broad spectrum antivirulence agents as exemplified by hit-to-lead optimization of one of the compounds.
A B S T R A C TA simple method for the synthesis of substituted selenopheno[2,3-c] and -[3,2-c]coumarins by treatment of the corresponding ethynylcoumarins with in situ prepared selenium(IV) bromide in 1,4-dioxane-water was elaborated. Molecular structures for selected derivatives were confirmed by X-ray diffraction measurements. The cytotoxic activity of novel selenophenocoumarins showed higher activity and lower acute toxicity than sodium selenite on various tumor cell lines as well as an ability for inhibiting matrix metalloproteinases (MMP-1 -MMP-14), angiogenesis on matrigel in vitro and in vivo. The compounds exhibit antioxidant and prooxidant properties.
Rapid spread of antibiotic resistance throughout the kingdom bacteria is inevitably bringing humanity towards the “post-antibiotic” era. The emergence of so-called “superbugs”—pathogen strains that develop resistance to multiple conventional antibiotics—is urging researchers around the globe to work on the development or perfecting of alternative means of tackling the pathogenic bacteria infections. Although various conceptually different approaches are being considered, each comes with its advantages and drawbacks. While drug-resistant pathogens are undoubtedly represented by both Gram(+) and Gram(−) bacteria, possible target spectrum across the proposed alternative approaches of tackling them is variable. Numerous anti-virulence strategies aimed at reducing the pathogenicity of target bacteria rather than eliminating them are being considered among such alternative approaches. Sortase A (SrtA) is a membrane-associated cysteine protease that catalyzes a cell wall sorting reaction by which surface proteins, including virulence factors, are anchored to the bacterial cell wall of Gram(+) bacteria. Although SrtA inhibition seems perspective among the Gram-positive pathogen-targeted antivirulence strategies, it still remains less popular than other alternatives. A decrease in virulence due to inactivation of SrtA activity has been extensively studied in Staphylococcus aureus, but it has also been demonstrated in other Gram(+) species. In this manuscript, results of past studies on the discovery of novel SrtA inhibitory compounds and evaluation of their potency were summarized and commented on. Here, we discussed the rationale behind the inhibition of SrtA, raised some concerns on the comparability of the results from different studies, and touched upon the possible resistance mechanisms as a response to implementation of such therapy in practice. The goal of this article is to encourage further studies of SrtA inhibitory compounds.
CCR2 is the cognate receptor to the chemokine CCL2. CCR2–CCL2 signaling mediates cancer progression and metastasis dissemination. However, the role of CCR2–CCL2 signaling in pathogenesis of B-cell malignancies is not clear. Previously, we showed that CCR2B was upregulated in ex vivo peripheral blood B cells upon Epstein‒Barr virus (EBV) infection and in established lymphoblastoid cell lines with the EBV latency III program. EBV latency III is associated with B-cell lymphomas in immunosuppressed patients. The majority of EBV-positive Burkitt lymphoma (BL) tumors are characterized by latency I, but the BL cell lines drift towards latency III during in vitro culture. In this study, the CCR2A and CCR2B expression was assessed in the isogenic EBV-positive BL cell lines with latency I and III using RT-PCR, immunoblotting, and immunostaining analyses. We found that CCR2B is upregulated in the EBV-positive BL cells with latency III. Consequently, we detected the migration of latency III cells toward CCL2. Notably, the G190A mutation, corresponding to SNP CCR2-V64I, was found in one latency III cell line with a reduced migratory response to CCL2. The upregulation of CCR2B may contribute to the enhanced migration of malignant B cells into CCL2-rich compartments.
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