Plasmodium falciparum parasites overexpressing farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase are more resistant to risedronate

Gabriel, Heloisa B.; Azevedo, Mauro Ferreira de; Kimura, Emı́lia A.; Katzin, Alejandro M.

doi:10.1590/0074-02760180174

Cited by 4 publications

(3 citation statements)

References 31 publications

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“…In agreement with these findings, recombinant FPPS from T. brucei and T. cruzi were found to be inhibited by risedronate [14,15]. Similar inhibitory effects of nitrogen containing bisphosphonates were observed against FPPS from T. gondii and P. falciparum [16][17][18].…”

Section: Introductionsupporting

confidence: 80%

Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major

Mukherjee

Basu

Zhang

2019

Molecular and Biochemical Parasitology

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Isoprenoid synthesis provides a diverse class of biomolecules including sterols, dolichols, ubiquinones and prenyl groups. The enzyme farnesyl pyrophosphate synthase (FPPS) catalyzes the formation of farnesyl pyrophosphate, a key intermediate for the biosynthesis of all isoprenoids. In Leishmania, FPPS is considered the main target of nitrogen containing bisphosphonates, yet the essentiality of this enzyme remains untested. Using a facilitated knockout approach, we carried out the genetic analysis of FPPS in Leishmania major. Our data indicated that chromosomal null mutants for FPPS could only be generated in presence of an episomally expressed FPPS. Longterm retention of the episome by the chromosomal FPPS-null mutants in culture and in infected BALB/c mice suggests that FPPS is indispensable. In addition, applying negative selection pressure failed to induce the loss of ectopic FPPS in the chromosomal FPPS-null mutants, although it led to significant growth delay in culture and in mice. Together, our findings have confirmed the essentiality of FPPS in both promastigotes and amastigotes in L. major and thus validate its potential as a drug target for the treatment of cutaneous leishmaniasis.

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Section: Introductionsupporting

confidence: 80%

Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major

Mukherjee

Basu

Zhang

2019

Molecular and Biochemical Parasitology

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“…The inhibitory effect can be partially reduced by addition of FPP or GPP during culture. Parasites overexpressing Pf FPPS/GGPPS are also more resistant to risedronate treatment. − This suggests that Pf FPPS/GGPPS is an important enzyme and presents a high-priority antimalarial drug target. Current bisphosphonate drugs show low selectivity for Pf FPPS/GGPPS and, due to their charged state, have poor bioavailability.…”

Section: Novel Antimalarial Drug Targetsmentioning

confidence: 99%

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Cheuka,

Njaria,

Mayoka

et al. 2024

J. Med. Chem.

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Approximately 619,000 malaria deaths were reported in 2021, and resistance to recommended drugs, including artemisinin-combination therapies (ACTs), threatens malaria control. Treatment failure with ACTs has been found to be as high as 93% in northeastern Thailand, and parasite mutations responsible for artemisinin resistance have already been reported in some African countries. Therefore, there is an urgent need to identify alternative treatments with novel targets. In this Perspective, we discuss some promising antimalarial drug targets, including enzymes involved in proteolysis, DNA and RNA metabolism, protein synthesis, and isoprenoid metabolism. Other targets discussed are transporters, Plasmodium falciparum acetyl-coenzyme A synthetase, N-myristoyltransferase, and the cyclic guanosine monophosphate-dependent protein kinase G. We have outlined mechanistic details, where these are understood, underpinning the biological roles and hence druggability of such targets. We believe that having a clear understanding of the underlying chemical interactions is valuable to medicinal chemists in their quest to design appropriate inhibitors. ■ SIGNIFICANCEFor the first time, we report some emerging antimalarial targets with special emphasis on mechanistic details of how they function. We believe such details are of value in medicinal chemistry toward facilitating rapid design of inhibitors. While considerable efforts have been made regarding drug target identification, the corresponding medicinal chemistry hit identification and hit-to-lead optimization have been insufficient. We believe this Perspective will contribute to bridging the gap between target discovery and inhibitor design.

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“…For example, overexpression of the molecular target can act as a sink, effectively mopping up the drug and promoting survival during drug treatment. This could be especially useful for identifying targets of inhibitors that are still in development (16) and has recently been used to identify a target of the antimalarial drug risedronate (17) and another antimalarial proteasome inhibitor (18). In basic biology, overexpression screens have been critical for discoveries in the areas of chromosome segregation, cell cycle, signal transduction, transcriptional regulation, cell polarity, and stem cell biology (19).…”

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confidence: 99%

A Trypanosoma brucei ORFeome-Based Gain-of-Function Library Identifies Genes That Promote Survival during Melarsoprol Treatment

Carter

Gomez

Gritz

et al. 2020

mSphere

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Trypanosoma brucei is an early branching protozoan parasite that causes human and animal African trypanosomiasis. Forward genetics approaches are powerful tools for uncovering novel aspects of trypanosomatid biology, pathogenesis, and therapeutic approaches against trypanosomiasis. Here, we have generated a T. brucei cloned ORFeome consisting of >90% of the targeted 7,245 genes and used it to make an inducible gain-of-function parasite library broadly applicable to large-scale forward genetic screens. We conducted a proof-of-principle genetic screen to identify genes whose expression promotes survival in melarsoprol, a critical drug of last resort. The 57 genes identified as overrepresented in melarsoprol survivor populations included the gene encoding the rate-limiting enzyme for the biosynthesis of an established drug target (trypanothione), validating the tool. In addition, novel genes associated with gene expression, flagellum localization, and mitochondrion localization were identified, and a subset of those genes increased melarsoprol resistance upon overexpression in culture. These findings offer new insights into trypanosomatid basic biology, implications for drug targets, and direct or indirect drug resistance mechanisms. This study generated a T. brucei ORFeome and gain-of-function parasite library, demonstrated the library’s usefulness in forward genetic screening, and identified novel aspects of melarsoprol resistance that will be the subject of future investigations. These powerful genetic tools can be used to broadly advance trypanosomatid research. IMPORTANCE Trypanosomatid parasites threaten the health of more than 1 billion people worldwide. Because their genomes are highly diverged from those of well-established eukaryotes, conservation is not always useful in assigning gene functions. However, it is precisely among the trypanosomatid-specific genes that ideal therapeutic targets might be found. Forward genetics approaches are an effective way to identify novel gene functions. We used an ORFeome approach to clone a large percentage of Trypanosoma brucei genes and generate a gain-of-function parasite library. This library was used in a genetic screen to identify genes that promote resistance to the clinically significant yet highly toxic drug melarsoprol. Hits arising from the screen demonstrated the library’s usefulness in identifying known pathways and uncovered novel aspects of resistance mediated by proteins localized to the flagellum and mitochondrion. The powerful new genetic tools generated herein are expected to promote advances in trypanosomatid biology and therapeutic development in the years to come.

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Plasmodium falciparum parasites overexpressing farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase are more resistant to risedronate

Cited by 4 publications

References 31 publications

Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major

Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

A Trypanosoma brucei ORFeome-Based Gain-of-Function Library Identifies Genes That Promote Survival during Melarsoprol Treatment

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