Plasmodium falciparum pyruvate kinase as a novel target for antimalarial drug-screening

Chan, Maurice; Tan, Doreen Su‐Yin; Sim, Timothy

doi:10.1016/j.tmaid.2006.01.015

Cited by 31 publications

(26 citation statements)

References 18 publications

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“…6, Table 3) was determined to be Ͼ4, indicating selectivity of these compounds for bacterial versus mammalian cells. Taken together, these findings showed that bis-indole-containing compounds C and D exhibited the most potent and selective inhibitory activity against bacterial PK enzyme with IC 50 and antibacterial activities (MIC) in the low nanomolar and micromolar range, respectively. Data obtained from these studies are summarized in Table 3.…”

Section: Mrsa Pkmentioning

confidence: 57%

“…The results demonstrated that compounds C and D displayed marked selectivity for bacterial PK. Inhibitory potencies, expressed as IC 50 values, were next determined for compounds C and D (Fig. 5).…”

Section: Resultsmentioning

confidence: 99%

“…Growth in compound-free control wells was considered as 100% and percentage of growth inhibition was calculated for each compound concentration. Cytotoxicity was quantified as the CC 50 , the concentration of compound that inhibited 50% of conversion of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) to formazan (32). The "selectivity index" is defined as the ratio of the mammalian cell cytotoxicity to the MIC against S. aureus (i.e.…”

Section: Methodsmentioning

confidence: 99%

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Methicillin-resistant Staphylococcus aureus (MRSA) Pyruvate Kinase as a Target for Bis-indole Alkaloids with Antibacterial Activities

Zoraghi

Worrall

See

et al. 2011

Journal of Biological Chemistry

115

142

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Background: Methicillin-resistant Staphylococcus aureus (MRSA) PK has been recently identified as a potential novel antimicrobial drug target. Results: Screening of a marine extract library led to the identification of several bis-indole alkaloids as novel potent and selective MRSA PK inhibitors. Conclusion:These results help to understand the mechanism of the antibacterial activities of marine bis-indole alkaloids. Significance: This study provides the basis for development of potential novel antimicrobials.

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Section: Mrsa Pkmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Methicillin-resistant Staphylococcus aureus (MRSA) Pyruvate Kinase as a Target for Bis-indole Alkaloids with Antibacterial Activities

Zoraghi

Worrall

See

et al. 2011

Journal of Biological Chemistry

115

142

View full text Add to dashboard Cite

show abstract

“…Pyruvate kinases catalyze the transfer of a phosphate group from PEP to ADP, forming pyruvate and ATP. Plasmodium and T. gondii possess two pyruvate kinases, a type I isoform (PKI) involved in glycolysis in the cytoplasm, and the type II isoform (PKII) of the apicoplast [115,119,120]. Like the pPTs, PKII is expected to support multiple aspects of apicoplast metabolism, providing pyruvate for both the FASII and DOXP pathways and ATP for a range of enzymatic reactions [112,117].…”

Section: Pyruvate Kinase (Pkii)mentioning

confidence: 99%

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Shears

Botté

McFadden

2015

Molecular and Biochemical Parasitology

104

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The malaria parasite Plasmodium possesses a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is essential for parasite survival, and harbors several plant-like metabolic pathways including a type II fatty acid synthesis (FASII) pathway. The FASII pathway was discovered in 1998, and much of the early research in the field pursued it as a therapeutic drug target. These studies identified a range of compounds with activity against bloodstage parasites and led to the localization and characterization of most enzymes in the pathway. However, when genetic studies revealed FASII was dispensable in bloodstage parasites, it effectively discounted the pathway as a therapeutic drug target, and suggested these compounds instead interfered with other processes. Interest in FASII then shifted toward its disruption for malaria prophylaxis and vaccine development, with experiments in rodent malaria models identifying a crucial role for the pathway in the parasite's transition from the liver to the blood. Unexpectedly however, the human malaria parasite P. falciparum was recently found to differ from rodent models and require FASII for mosquito stage development. This requirement blocked the production of the FASII-deficient forms that might be used as a genetically attenuated parasite vaccine, suggesting the pathway was also unsuitable as a vaccine target. This review discusses how perception of FASII has changed over time, and presents key findings about each enzyme in the pathway to identify remaining questions and opportunities for malaria control.

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“…Furthermore, despite the high degree of similarity between eukaryotic PKs, they have recently been drawing a lot of attention as novel targets for antitrypanosomal, antileishmanial, and antimalarial drugs (6,8,9,26,27). Therefore, sequence divergence between MRSA PK and human PKs is of particular interest for the design of selective inhibitors that specifically target the bacterial enzyme.…”

Section: Vol 55 2011mentioning

confidence: 99%

Identification of Pyruvate Kinase in Methicillin-Resistant Staphylococcus aureus as a Novel Antimicrobial Drug Target

Zoraghi

See

Axerio-Cilies

et al. 2011

Antimicrob Agents Chemother

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Novel classes of antimicrobials are needed to address the challenge of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). Using the architecture of the MRSA interactome, we identified pyruvate kinase (PK) as a potential novel drug target based upon it being a highly connected, essential hub in the MRSA interactome. Structural modeling, including X-ray crystallography, revealed discrete features of PK in MRSA, which appeared suitable for the selective targeting of the bacterial enzyme. In silico library screening combined with functional enzymatic assays identified an acyl hydrazone-based compound (IS-130) as a potent MRSA PK inhibitor (50% inhibitory concentration [IC 50 ] of 0.1 M) with >1,000-fold selectivity over human PK isoforms. Medicinal chemistry around the IS-130 scaffold identified analogs that more potently and selectively inhibited MRSA PK enzymatic activity and S. aureus growth in vitro (MIC of 1 to 5 g/ml). These novel anti-PK compounds were found to possess antistaphylococcal activity, including both MRSA and multidrug-resistant S. aureus (MDRSA) strains. These compounds also exhibited exceptional antibacterial activities against other Gram-positive genera, including enterococci and streptococci. PK lead compounds were found to be noncompetitive inhibitors and were bactericidal. In addition, mutants with significant increases in MICs were not isolated after 25 bacterial passages in culture, indicating that resistance may be slow to emerge. These findings validate the principles of network science as a powerful approach to identify novel antibacterial drug targets. They also provide a proof of principle, based upon PK in MRSA, for a research platform aimed at discovering and optimizing selective inhibitors of novel bacterial targets where human orthologs exist, as leads for anti-infective drug development.

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Plasmodium falciparum pyruvate kinase as a novel target for antimalarial drug-screening

Cited by 31 publications

References 18 publications

Methicillin-resistant Staphylococcus aureus (MRSA) Pyruvate Kinase as a Target for Bis-indole Alkaloids with Antibacterial Activities

Methicillin-resistant Staphylococcus aureus (MRSA) Pyruvate Kinase as a Target for Bis-indole Alkaloids with Antibacterial Activities

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Identification of Pyruvate Kinase in Methicillin-Resistant Staphylococcus aureus as a Novel Antimicrobial Drug Target

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