Cis-2 and trans-2-eisocenoic fatty acids are novel inhibitors for Mycobacterium tuberculosis Protein tyrosine phosphatase A

Savalas, Lalu Rudyat Telly; Furqon, Baiq Repika Nurul; Asnawati, Dina; ‘Ardhuha, Jannatin; Sedijani, Prapti; Hadisaputra, Saprizal; Ningsih, Baiq Nila Sari; Syahri, Jufrizal

doi:10.18388/abp.2020_5201

Cited by 3 publications

(4 citation statements)

References 22 publications

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“…It is noteworthy that while we have found two naphthoquinones as inhibitors of Mt-PTPa in this study, earlier studies have identified other compounds that have specific inhibitory effects on Mt-PTPa. Examples include synthetic chalcones [ 65 , 66 ], phenyl azole derivatives [ 67 ], thiosemicarbazides [ 12 ], and Cis-2 and trans-2-eicosenoic fatty acids [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa)

Sulyman,

Fulcher,

Crossley

et al. 2023

BioTech

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Low-molecular-weight protein tyrosine phosphatases (LMW-PTPs) are involved in promoting the intracellular survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis. These PTPs directly alter host signalling pathways to evade the hostile environment of macrophages and avoid host clearance. Among these, protein tyrosine phosphatase A (Mt-PTPa) is implicated in phagosome acidification failure, thereby inhibiting phagosome maturation to promote Mycobacterium tuberculosis (Mtb) survival. In this study, we explored Mt-PTPa as a potential drug target for treating Mtb. We started by screening a library of 502 pure natural compounds against the activities of Mt-PTPa in vitro, with a threshold of 50% inhibition of activity via a <500 µM concentration of the candidate drugs. The initial screen identified epigallocatechin, myricetin, rosmarinic acid, and shikonin as hits. Among these, the naphthoquinone, shikonin (5, 8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-1,4-naphthoquinone), showed the strongest inhibition (IC50 33 µM). Further tests showed that juglone (5-hydroxy-1,4-naphthalenedione), another naphthoquinone, displayed similar potent inhibition of Mt-PTPa to shikonin. Kinetic analysis of the inhibition patterns suggests a non-competitive inhibition mechanism for both compounds, with inhibitor constants (Ki) of 8.5 µM and 12.5 µM for shikonin and juglone, respectively. Our findings are consistent with earlier studies suggesting that Mt-PTPa is susceptible to specific allosteric modulation via a non-competitive or mixed inhibition mechanism.

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Section: Discussionmentioning

confidence: 99%

Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa)

Sulyman,

Fulcher,

Crossley

et al. 2023

BioTech

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“…A lead compound against PtpA, L335-M34 (, ), has an IC 50 of 160 nM and shows significant synergy when used in combination with isoniazid (INH), RIF and pyrazinamide in the guinea pig model [60]. A more recent publication demonstrated that activity of PtpA was inhibited by cis -2 and trans -2 eicosenoic fatty acids, with both compounds showing inhibition of PtpA, with IC50 at 8.20 and 11.26 µM, respectively [63]. Hydrogen bond-mediated binding activity was postulated via in silico modelling.…”

Section: Introductionmentioning

confidence: 99%

“…Thioredoxin reductase (TrxB2), an important protein for oxidative stress defence, is also a substrate of PtkA [ 63 ]. Interestingly, the human homologue, TRXB2, has been speculated to play a major role in oxidative stress (OS) defence during Mtb infection, making compound development against TrxB2 difficult [ 66 ].…”

Section: Introductionmentioning

confidence: 99%

From infection niche to therapeutic target: the intracellular lifestyle of Mycobacterium tuberculosis

2021

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Mycobacterium tuberculosis (Mtb) is an obligate human pathogen killing millions of people annually. Treatment for tuberculosis is lengthy and complicated, involving multiple drugs and often resulting in serious side effects and non-compliance. Mtb has developed numerous complex mechanisms enabling it to not only survive but replicate inside professional phagocytes. These mechanisms include, among others, overcoming the phagosome maturation process, inhibiting the acidification of the phagosome and inhibiting apoptosis. Within the past decade, technologies have been developed that enable a more accurate understanding of Mtb physiology within its intracellular niche, paving the way for more clinically relevant drug-development programmes. Here we review the molecular biology of Mtb pathogenesis offering a unique perspective on the use and development of therapies that target Mtb during its intracellular life stage.

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“…It has recently been shown that cis-2 and trans-2eicosenoic fatty acids can inhibit PtpA (19). A few reports suggest that PtpA and PtpB have common inhibitors, although the inhibitory effect may vary (20).…”

Section: Introductionmentioning

confidence: 99%

cis-2 and trans-2-eicosenoic Fatty Acids Inhibit Mycobacterium tuberculosis Virulence Factor Protein Tyrosine Phosphatase B

Savalas

Lestari²,

Munirah

et al. 2021

Journal of the Turkish Chemical Society Section A: Chemistry

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The present study aims to investigate the potential inhibitory effect of eicosenoic fatty acids on protein tyrosine phosphatase B of Mycobacterium tuberculosis (PtpB). PtpB is recognized to play a vital role in Mycobacterium tuberculosis (Mtb) successful latent infection. It prevents the fusion even between phagocytosed mycobacteria with lysosomes so that the bacteria escape from degradation. We have overexpressed recombinant Mtb PtpB within Escherichia coli BL21(DE3), and further, we have used the protein for inhibition assay with cis-2 and trans-eicosenoic fatty acids. It is revealed that at a concentration of 16 µM, cis-2-and trans-2-eicosenoic fatty acids can inhibit PtpB by 63.72% and 74.67%, respectively. Docking analysis has confirmed strong interactions of PtpB with cis-2 and trans-2-eicosenoic fatty acids, with the binding energy of -60.40 and -61.60 kcal/mol, respectively. These findings underline both fatty acids' high potential to be further investigated to discover drugs against latent tuberculosis infection.

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Cis-2 and trans-2-eisocenoic fatty acids are novel inhibitors for Mycobacterium tuberculosis Protein tyrosine phosphatase A

Cited by 3 publications

References 22 publications

Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa)

Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa)

From infection niche to therapeutic target: the intracellular lifestyle of Mycobacterium tuberculosis

cis-2 and trans-2-eicosenoic Fatty Acids Inhibit Mycobacterium tuberculosis Virulence Factor Protein Tyrosine Phosphatase B

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