Design and synthesis of novel anti-tuberculosis agents from the celecoxib pharmacophore

Salunke, Santosh B.; Azad, Abul K.; Kapuriya, Naval; Balada-Llasat, Joan-Miquel; Pancholi, Preeti; Schlesinger, Larry S.; Chen, Ching‐Shih

doi:10.1016/j.bmc.2015.03.041

Cited by 33 publications

(41 citation statements)

References 41 publications

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“…The mCherry- M.tb strain was kindly provided by Dr. Sarah Fortune, Harvard University. A luciferase-expressing reporter strain of M.tb ( M.tb -Lux) was used in which the plasmid construct pMV306hsp+Lux (which contains the entire bacterial Lux operon cloned in a mycobacterial integrative expression vector) was introduced into M.tb H 37 R v (Andreu et al, 2010; Salunke et al, 2015; Guirado et al, 2015). The concentration of bacteria (1–2 × 10 8 bacteria /ml) and the degree of clumping (≤10%) were determined by counting in a Petroff-Hausser chamber.…”

Section: Methodsmentioning

confidence: 99%

M. tuberculosis -Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1

et al. 2017

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Summary Despite its prominent role as C-type lectin (CTL) pattern recognition receptor, mannose receptor (MR, CD206)-specific signaling molecules and pathways are unknown. The MR is highly expressed on human macrophages, regulating endocytosis, phagocytosis and immune responses, and mediating Mycobacterium tuberculosis (M.tb) phagocytosis by human macrophages thereby limiting phagosome-lysosome (P-L) fusion. We identified human MR-associated proteins using phosphorylated and non-phosphorylated MR cytoplasmic tail peptides. We found that MR binds FcRγ-chain, which is required for MR plasma membrane localization and M.tb cell association. Additionally, we discovered that MR-mediated M.tb association triggers immediate MR tyrosine residue phosphorylation and Grb2 recruitment, activating the Rac/Pak/Cdc-42 signaling cascade important for M.tb uptake. MR activation subsequently recruits SHP-1 to the M.tb-containing phagosome, where its activity limits PI(3)P generation at the phagosome and M.tb P-L fusion, and promotes M.tb growth. In sum, we identify human MR signaling pathways that temporally regulate phagocytosis and P-L fusion during M.tb infection.

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Section: Methodsmentioning

confidence: 99%

M. tuberculosis -Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1

et al. 2017

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“…M.tb H 37 R v (ATCC #25618) and a luciferase expressing reporter strain ( M.tb -Lux) containing the plasmid pMV306hsp+Lux (59) were used (56). Day 6 MDMs (4 x 10 5 /ml) were seeded in a 24 well tissue culture plate and either exposed to Survanta (100 μg/ml) for 48h prior to infection or transfected with scramble or CD36 siRNA for 48h and then exposed to Survanta for 24h.…”

Section: Methodsmentioning

confidence: 99%

“…Monolayers were washed, repleted with RPMI containing 2% autologous serum and incubated up to 72h. Bacterial growth was measured by luciferase activity (59) or supernatants were collected for ELISAs.…”

Section: Methodsmentioning

confidence: 99%

CD36-Mediated Uptake of Surfactant Lipids by Human Macrophages Promotes Intracellular Growth of Mycobacterium tuberculosis

Dodd

Pyle

Glowinski

et al. 2016

The Journal of Immunology

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Mycobacterium tuberculosis (M.tb) imposes a large global health burden as the airborne agent of tuberculosis. M.tb has been flourishing in human populations for millennia and is therefore highly adapted to the lung environment. Alveolar macrophages (AMs), a major host cell niche for M.tb, not only phagocytose inhaled microbes and particulate matter but are also crucial in catabolizing lung surfactant, a lipid-protein complex that lines the alveolar spaces. Since macrophage host defense properties can be regulated by surfactant and M.tb can use host lipids as a carbon source during infection, we sought to determine the receptor(s) involved in surfactant lipid uptake by human macrophages and whether the presence of those lipids within macrophages prior to infection with M.tb enhances bacterial growth. We show that preformed scavenger receptor CD36 is redistributed to the cell membrane following exposure to surfactant lipids and surfactant protein A (SP-A). Subsequently, surfactant lipids and/or SP-A enhance CD36 transcript and protein levels. We show that CD36 participates in surfactant lipid uptake by human macrophages, as CD36 knockdown reduces uptake of dipalmitoylphosphatidylcholine (DPPC), the most prevalent surfactant lipid species. Finally, exposing human macrophages to surfactant lipids prior to infection augments M.tb growth in a CD36-dependent manner. Thus, we provide evidence that CD36 mediates surfactant lipid uptake by human macrophages and that M.tb exploits this function for growth.

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“…M. tuberculosis H 37 R v [luciferase expressing (23)] was cultured in 7H9 media plus OADC containing 0.05% Tween-80 at 37˚C shaking ∼50 rpm M. tuberculosis was prepared and used to infect mice similarly to M. bovis BCG infection described above. Mice were infected by an intranasal inoculation of 50 ml containing ∼0.1 to 1.0 3 10 2 bacilli, as confirmed by plating on 7H11 agar (Sigma-Aldrich).…”

Section: Tuberculosis In Vivo Infectionmentioning

confidence: 99%

l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

Lange

McKell

Schmidt

et al. 2019

The Journal of Immunology

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Immunonutrition as a therapeutic approach is rapidly gaining interest in the fight against infection. Targeting l-arginine metabolism is intriguing, considering this amino acid is the substrate for antimicrobial NO production by macrophages. The importance of l-arginine during infection is supported by the finding that inhibiting its synthesis from its precursor l-citrulline blunts host defense. During the first few weeks following pulmonary mycobacterial infection, we found a drastic increase in l-citrulline in the lung, even though serum concentrations were unaltered. This correlated with increased gene expression of the l-citrulline–generating (i.e., iNOS) and l-citrulline–using (i.e., Ass1) enzymes in key myeloid populations. Eliminating l-arginine synthesis from l-citrulline in myeloid cells via conditional deletion of either Ass1 or Asl resulted in increased Mycobacterium bovis bacillus Calmette-Guérin and Mycobacterium tuberculosis H37Rv burden in the lungs compared with controls. Our data illustrate the necessity of l-citrulline metabolism for myeloid defense against mycobacterial infection and highlight the potential for host-directed therapy against mycobacterial disease targeting this nutrient and/or its metabolic pathway.

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Design and synthesis of novel anti-tuberculosis agents from the celecoxib pharmacophore

Cited by 33 publications

References 41 publications

M. tuberculosis -Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1

M. tuberculosis -Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1

CD36-Mediated Uptake of Surfactant Lipids by Human Macrophages Promotes Intracellular Growth of Mycobacterium tuberculosis

l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

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