The synthesis and biological evaluation of mycobacterial p-hydroxybenzoic acid derivatives (p-HBADs)

Bourke, J. A.; Brereton, Corinna F.; Gordon, Stephen V.; Lavelle, Ed C.; Scanlan, Eoin M.

doi:10.1039/c3ob42277a

Cited by 20 publications

(33 citation statements)

References 44 publications

(73 reference statements)

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“…These results are in agreement with our earlier work on synthetic analogues from M. leprae and M. bovis 17 and, taken together, demonstrate that the glycan portion of PGLs alone can inhibit release of the evaluated cytokines and NO. This conclusion is further supported by a recent investigation on p ‐HBAD‐I and p ‐HBAD‐II 19. In this study, Scanlan and co‐workers showed that p ‐HBAD‐I and an analogue lacking the methyl group on the rhamnose moiety exhibit an inhibitory effect on the release of some cytokines, in particular TNF‐α and IL‐12p40.…”

Section: Discussionsupporting

confidence: 76%

“…We report here the synthesis of a similar panel of analogues of known PGLs from M. tuberculosis ( 1 – 3 , Scheme ),7, 18 and an evaluation of their ability to modulate the production of various cytokines and nitric oxide (NO). This work complements a very recent study by Scanlan and co‐workers on p ‐HBAD‐I and p ‐HBAD‐II obtained by chemical synthesis 19…”

Section: Introductionsupporting

confidence: 82%

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Transatlantic Frontiers of Chemistry Symposium 2013 in Germany

2013

Nachr Chem

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Infection by Mycobacterium tuberculosis causes tuberculosis, a disease characterized by alteration of host innate and adaptive immunity. These processes are mediated by a series of bacterial biomolecules, among which phenolic glycolipids (PGLs) and the related p‐hydroxybenzoic acid derivatives have been suggested to play important roles. To probe the importance of structural features of these glycans on cytokine modulation, we synthesized three M. tuberculosis PGL analogues (1–3), which differ from the native glycoconjugates by possessing a simplified lipid algycone. The ability of 1–3 to modulate the release of proinflammatory cytokines (TNF‐α, IL‐1β, IL‐6, MCP‐1) and nitric oxide (NO) was evaluated. None of the compounds stimulated the secretion of these signalling molecules. However, all showed a Toll‐like Receptor 2‐mediated, concentration‐dependent inhibition profile that was related to the methylation pattern on the glycan.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionsupporting

confidence: 82%

Transatlantic Frontiers of Chemistry Symposium 2013 in Germany

2013

Nachr Chem

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“… 47 Moreover, chemically synthesized p -HBAD-I and II have been shown to suppress T-cell proliferation and activation, and block the production of pro-inflammatory cytokines by irradiated M. tb -stimulated murine bone marrow-derived macrophages in vitro. 48 Given the overwhelming evidence that many individual mycobacterial glycolipids and glycans individually display immunomodulatory properties, their overall effect on the host immune system when immunostimulatory mycobacterial Ags are also present, remain to be ascertained and warrant further study.…”

Section: Discussionmentioning

confidence: 99%

Poor stimulation of bovine dendritic cells by Mycobacterium bovis culture supernatant and surface extract is associated with decreased activation of ERK and NF-κB and higher expression of SOCS1 and 3

2020

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The cell envelope of pathogenic mycobacteria interfaces with the host. As such, the interaction of bacterial products localized at or released from the cell surface with the host’s immune system can determine the fate of the bacterium in its host. In this study, the effects of three different types of Mycobacterium bovis cell envelope fractions—purified protein derivative, total cell wall lipids and culture supernatant and surface extract—on bovine dendritic cells were assessed. We found that the culture supernatant and surface extract fraction induced little to no production of the pro-inflammatory cytokines TNF-α and IL-12 in bovine dendritic cells. Moreover, this muted response was associated with poor activation of ERK and NF-κB, both of which are critical for the pro-inflammatory response. Furthermore, culture supernatant and surface extract treatment increased the expression of suppressor of cytokine signaling 1 and 3, both of which are negative regulators of pro-inflammatory signaling, in bovine dendritic cells. These observations taken together suggest the M. bovis culture supernatant and surface extract fraction contain immunomodulatory molecules that may aid in M. bovis pathogenesis.

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“…Mycobacterium tuberculosis secretes a complex variety of glycosylated compounds present in the cell wall during infection which acts as immunomodulatory molecules. p-hydroxybenzoic acid derivatives (p-HBADs) are synthesized by Mycobacterium tuberculosis to inhibit the production of inflammatory cytokines, particularly interferon-γ (IFNγ) by T-cells [18]. Mycobacterium tuberculosis controls the host cell machinery through its transcription factor sigma-E involved in the modulation of the host inflammatory response against the pathogen.…”

Section: Inhibition Of Inflammation As a Survival Strategy For Mycobamentioning

confidence: 99%

Dual Role of Inflammation in Prognosis and Prevention of Tuberculosis

Majeed¹,

Mir²,

Sharma³

2015

J Clin Cell Immunol

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The high death rate and progressive spread of tuberculosis emphasizes the need to address the complexities associated with the disease and its treatment. Complications associated with the disease are associated with the process of inflammation. Host defense system protects the body against pathogen by various inflammatory responses and the same are utilized by the pathogen as an offensive tool to progress inside the host. The genetic factors which determine the expression of inflammatory markers affect the onset of the disease and its treatment. The susceptibility to infection, progression to active or latent form and dissemination to the other sites are governed by the inflammatory responses generated by the host. The prognosis of tuberculosis is not the pathogenic infection but the outcome of the host-pathogen interactions, most of which are still not understood. In this review we discuss the major host inflammatory responses during Mycobacterium tuberculosis infection and their role in progression and/or containment of the infection. In addition the possible role of anti-inflammatory drugs as adjunct to the current anti-tuberculosis treatment will be reviewed.

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The synthesis and biological evaluation of mycobacterial p-hydroxybenzoic acid derivatives (p-HBADs)

Abstract: Synthetic p-hydroxybenzoic acid derivatives (p-HBADs) from Mycobacterium tuberculosis have the ability to suppress host immune response in vitro.

Cited by 20 publications

References 44 publications

Transatlantic Frontiers of Chemistry Symposium 2013 in Germany

Transatlantic Frontiers of Chemistry Symposium 2013 in Germany

Poor stimulation of bovine dendritic cells by Mycobacterium bovis culture supernatant and surface extract is associated with decreased activation of ERK and NF-κB and higher expression of SOCS1 and 3

Dual Role of Inflammation in Prognosis and Prevention of Tuberculosis

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