High Throughput Screen Identifies Small Molecule Inhibitors Specific for Mycobacterium tuberculosis Phosphoserine Phosphatase

Arora, Garima; Tiwari, Priya; Mandal, Rahul Shubhra; Gupta, A. P.; Sharma, Deepak; Saha, Sudipto; Singh, Ramandeep

doi:10.1074/jbc.m114.597682

Cited by 31 publications

(33 citation statements)

References 56 publications

(48 reference statements)

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“…Greater clorobiocin efficacy may be the result of stronger enzyme inhibition by clorobiocin as previously shown against the DNA gyrase and topoisomerase IV proteins from both E. coli and Staphylococcus aureus [21]. Alternatively, differences between novobiocin and clorobiocin might be due to other clorobiocin targets, for example clorobiocin can inhibit the phosphoserine phosphatase SerB2 of Mycobacterium tuberculosis while novobiocin cannot [22].…”

Section: Discussionmentioning

confidence: 99%

Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia

Loutet

El-Halfawy

Jassem

et al. 2015

International Journal of Antimicrobial Agents

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Burkholderia cenocepacia and other members of the Burkholderia cepacia complex (Bcc) are highly multidrug-resistant bacteria that cause severe pulmonary infections in patients with cystic fibrosis. A screen of 2686 compounds derived from marine organisms identified molecules that could synergize with polymyxin B to inhibit growth of B. cenocepacia. At 1 µg/ml, five compounds synergized with polymyxin B and inhibited the growth of B. cenocepacia by more than 70% compared to growth in polymyxin B alone. Follow-up testing revealed that one compound from the screen, the aminocoumarin antibiotic novobiocin, synergized with polymyxin B and colistin against tobramycin-resistant clinical isolates of B. cenocepacia and Burkholderia multivorans. In parallel, we show that novobiocin sensitivity is common among Bcc species and these bacteria are even more susceptible to an alternative aminocoumarin, clorobiocin, which also had an additive effect with polymyxin B against B. cenocepacia. These studies support using aminocoumarin antibiotics to treat Bcc infections and show that synergizers can be found to increase the efficacy of antimicrobial peptides and polymyxins against Bcc bacteria.

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Section: Discussionmentioning

confidence: 99%

Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia

Loutet

El-Halfawy

Jassem

et al. 2015

International Journal of Antimicrobial Agents

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“…Initially characterized as an enzyme involved in the dephosphorylation of O-phospho-L-serine to L-serine [31], MtSerB2 has been recently shown to be secreted into the cytoplasm of infected THP1 cells and is hypothesized to help the bacterium in immune invasion and evasion [30]. SerB2 belongs to the haloacid dehalogenase (HAD) class of enzymes.…”

Section: Serb2mentioning

confidence: 99%

“…In the first report on MtSerB2, Arora et al [31] biochemically characterized the enzyme and showed that MtSerB2 displayed a preference toward O-phospho-L-serine over O-phospho-L-threonine. Through high throughput screening using 2300 compounds, they identified Clorobiocin and Rosalinine as the specific inhibitors against MtSerB2.…”

Section: Serb2mentioning

confidence: 99%

Bacterial Virulence Factors: Secreted for Survival

et al. 2016

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Virulence is described as an ability of an organism to infect the host and cause a disease. Virulence factors are the molecules that assist the bacterium colonize the host at the cellular level. These factors are either secretory, membrane associated or cytosolic in nature. The cytosolic factors facilitate the bacterium to undergo quick adaptive-metabolic, physiological and morphological shifts. The membrane associated virulence factors aid the bacterium in adhesion and evasion of the host cell. The secretory factors are important components of bacterial armoury which help the bacterium wade through the innate and adaptive immune response mounted within the host. In extracellular pathogens, the secretory virulence factors act synergistically to kill the host cells. In this review, we revisit the role of some of the secreted virulence factors of two human pathogens: Mycobacterium tuberculosis-an intracellular pathogen and Bacillus anthracis-an extracellular pathogen. The advances in research on the role of secretory factors of these pathogens during infection are discussed.

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“…Earlier studies have also shown that MtSerB2 represents a new druggable target [5,28]. As part of evaluation of compounds from the Prestwick Chemical Library, we prioritized studies on Clofazimine (CFZ), based on ongoing and reported evaluation of riminophenazine analogs by the TB alliance and other studies, against MDR and XDR TB infection [9].…”

Section: Identification Of Clofazimine (Cfz) As a Potent Inhibitor Ofmentioning

confidence: 99%

The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited by Clofazimine

Shree

Singh

Saxena

et al. 2016

Cell. Mol. Life Sci.

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Mycobacterium tuberculosis codes for a HAD-phosphatase, Rv3042c (MtSerB2), that has earlier been characterized as a metabolic enzyme. Here we demonstrate that MtSerB2 is secreted into the cytosol of infected macrophages and is found in bronchoalveolar lavage samples of tuberculosis patients. MtSerB2 induces significant cytoskeleton rearrangements through cofilin activation and affects the expression of genes that regulate actin dynamics. It specifically interacts with HSP90, HSP70 and HSP27 that block apoptotic pathways and not with other HSPs. It actively dephosphorylates MAPK-p38 and NF-kappa B p65 that play crucial roles in inflammatory and immune responses. This in turn leads to down-regulation of Interleukin 8, a chemotactic and inflammatory cytokine. Finally, during evaluation of inhibitors against MtSerB2 we found that Clofazimine, a drug being evaluated for XDR and MDR tuberculosis, inhibits MtSerB2 phosphatase activity and reverses the above effects and interactions with host proteins. Overall, the study identifies that MtSerB2 has new functions that might help the pathogen to evade the host's immune response.

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High Throughput Screen Identifies Small Molecule Inhibitors Specific for Mycobacterium tuberculosis Phosphoserine Phosphatase

Cited by 31 publications

References 56 publications

Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia

Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia

Bacterial Virulence Factors: Secreted for Survival

The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited by Clofazimine

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