Disruption of <i>mptpB</i> impairs the ability of <i>Mycobacterium tuberculosis</i> to survive in guinea pigs

Singh, Ramandeep; Rao, Vivek; Shakila, Harshavardhan; Gupta, Radhika; Khera, Aparna; Dhar, Neeraj; Singh, Amit Kumar; Koul, Anil; Singh, Yogendra; Naseema, M.; Narayanan, P R; Paramasivan, C. N.; Ramanathan, V. D.; Tyagi, Anil K.

doi:10.1046/j.1365-2958.2003.03712.x

Cited by 156 publications

(149 citation statements)

References 38 publications

(47 reference statements)

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“…Unfortunately, how Mtb evades the host immune responses remains unknown. Given the observation that Mtb-lacking mPTPB are unable to survive in macrophages and in guinea pig (11), it has been hypothesized that mPTPB may promote mycobacterial survival in the host by targeting the IFN-γ mediated signaling pathway, although the exact mechanism by which this occurs has not been elucidated. Since mPTPB functions within the macrophage, we established Raw264.7 mouse macrophage cell lines stably expressing mPTPB in order to investigate the role of mPTPB in host cell biology.…”

Section: Resultsmentioning

confidence: 99%

“…Given the absence of endogenous tyrosine phosphorylation within Mtb, mPTPA and mPTPB likely modify macrophage proteins to manipulate host-pathogen interactions. Interestingly, genetic deletion of mPTPB blocks intracellular survival of Mtb in interferon-γ (IFN-γ) activated macrophages and severely reduces the bacterial load in a clinically relevant guinea pig model of TB infection (11). These findings led to the hypothesis that mPTPB might mediate mycobacterial survival in macrophages by targeting host cell processes, although the underlying molecular basis is not understood.…”

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confidence: 99%

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Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Zhou¹,

He²,

Zhang

et al. 2010

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

215

205

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Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.combinatorial chemistry | pathogen-host interaction | phosphatase inhibitor | signaling mechanism

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Zhou¹,

He²,

Zhang

et al. 2010

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

215

205

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“…It uses its own PtdInsmannoside to inhibit PtdIns3P production (256) but also secretes a phosphatase, called SapM capable of dephosphorylating PtdIns3P (1630). Another phosphatase, MptpB, which is an important virulence factor of Mycobacterium tuberculosis (1411), is a trifunctional enzyme that hydrolyzes phosphoserine/threonines, phosphotyrosines, and phosphoinositides (120,121). While inhibiting PtdIns3P production of the host, Mycobacteria also synthesize PtdIns3P (1085), apparently as an intermediate of PtdIns synthesis and not as a result of PtdIns phosphorylation (1084).…”

Section: B Infectious Diseasesmentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,359

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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“…In this experiment, it was found that the disruption of mPTPB gene resulted in 70-fold reduction in the bacterial load in the spleen of guinea pigs. Complementary strain, obtained after reintroducing the gene into the mutant strain, regained the ability to infect the guinea pigs at rates comparable to the parent strain [8]. Beresford et al also studied the growth of mycobacteria in resting macrophages in order to mimic the infection in a susceptible host (where IFNγ activation may be impaired).…”

Section: Introductionmentioning

confidence: 99%

Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors

et al. 2014

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BackgroundTuberculosis has become a major health problem being the second leading cause of death worldwide. Mycobacterium tuberculosis secretes a virulence factor, protein tyrosine phosphatase B (mPTPB) in the cytoplasm of host macrophage which suppresses its natural innate immune response and helps the pathogen survive and proliferate in the phagosome. The present study aims at indentifying potent inhibitors of mPTPB by using computational approaches of ligand based molecular modeling and docking studies.ResultsA 3D QSAR model was developed using a set of benzofuran salicylic acid based mPTPB inhibitors with experimentally known IC50 values. The model was generated using the statistical method of principle component regression analysis in combination with step wise forward variable selection algorithm. It was observed that steric and hydrophobic descriptors positively contribute towards the inhibitory activity of the ligands. The developed model had a robust internal as well as external predictive power as indicated by the q2 value of 0.8920 and predicted r2 value of 0.8006 respectively. Hence, the generated model was used to screen a large set of naturally occurring chemical compounds and predict their biological activity to identify more potent natural compounds targeting mPTPB. The two top potential hits (with pIC50 value of 1.459 and 1.677 respectively) had a similar interaction pattern as that of the most potent compound (pIC50 = 1.42) of the congeneric series.ConclusionThe contour plot provided a better understanding of the relationship between structural features of substituted benzofuran salicylic acid derivatives and their activities which would facilitate design of novel mPTPB inhibitors. The QSAR modeling was used to obtain an equation, correlating the important steric and hydrophobic descriptors with the pIC50 value. Thus, we report two natural compounds of inhibitory nature active against mPTPB enzyme of Mycobacterium tuberculosis. These inhibitors have the potential to evolve as lead molecules in the development of drugs for the treatment of tuberculosis.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-S1-S3) contains supplementary material, which is available to authorized users.

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Disruption of mptpB impairs the ability of Mycobacterium tuberculosis to survive in guinea pigs

Cited by 156 publications

References 38 publications

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors

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