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Principal Investigator: Shirley Luckhart
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2024
Award: $616,676
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Malaria parasites require pantothenate (Pan) from both the insect and mammalian hosts to synthesize
coenzyme A (CoA) and acetyl-CoA (AC). Further, mosquito-stage parasites cannot take up preformed CoA
from the insect host, so they are entirely dependent on mosquito Pan availability. Thus, we hypothesize that
reducing Pan stores in the mosquito by increasing Pan kinase (PanK) activity and, in turn, CoA biosynthesis
will limit parasite survival in the mosquito, without impacting the availability of CoA/AC to the mosquito itself.
PanK is the rate-limiting enzyme in the CoA biosynthesis pathway and a logical target for our approach. In this
study we will focus on increasing PanK activity in the mosquito to convert Pan into CoA and starve the malaria
parasite of this essential precursor. To accomplish this we will utilize PanK-targeted small molecules or
pantazines and genetic manipulation of PanK in our study host Anopheles stephensi. We will screen
pantazines from a library of compounds developed by our collaborators at St. Jude Children’s Hospital. In
Aim 1, we will use a Go-No Go strategy for pantazine screening that culminates in testing the capacity of
selected pantazines to reduce P. falciparum and Plasmodium yoelii infections in A. stephensi. Aim 2 will
validate the bioactivity and specificity of candidate pantazines identified in the screen in Aim 1. The specificity
of candidate pantazines to activate PanK will be assessed through RNAi or CRISPR/Cas9 knockdown of
PanK, followed by a characterization of the impact on Pan, CoA, AC and parasite infection success.
Concurrent with Aims 1 and 2, we will generate transgenic A. stephensi with increased PanK activity and
determine the impact on Pan levels and parasite survival in Aim 3. The generation of transgenic mosquitoes
with increased midgut PanK expression will contribute to our assessment of PanK-dependent depletion of Pan
stores on parasite infection as well as other aspects of mosquito biology related to vectorial capacity.
Specifically, we will define the effects of mosquito PanK activation, via both pantazine treatment and molecular
manipulations, on A. stephensi lifespan, stress responses, metabolism and reproduction. These studies will
reveal important new insights into nutrient-driven mosquito-parasite interactions that drive parasite infection
success and they will support future efforts to optimize pantazines and novel transgenic lines as distinct
strategies for mosquito-targeted malaria control.
Terms: <ATP-protein phosphotransferase><Acetyl CoA><Acetyl Coenzyme A><Affect><Anabolism><Anopheles><Anopheles Genus><Anophelines><Binding><Biology><Blood><Blood Reticuloendothelial System><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Communication and Signaling><Cell Signaling><Chemicals><Children's Hospital><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><CoA><Coenzyme A><Culicidae><Daphnia><Data><Development><Drosophila><Drosophila genus><Drug Therapy><Drug resistance><Drugs><Engineering><Enzyme Gene><Enzymes><Exhibits><Future><Generalized Growth><Generations><Genetic><Goals><Growth><Hereditary><Homology Modeling><Human><In Vitro><Infection><Inherited><Insecta><Insecticide Resistance><Insects><Insects Invertebrates><Intermediary Metabolism><Intracellular Communication and Signaling><Kinase Family Gene><Lead><Libraries><MMAC1><MMAC1 protein><Malaria><Medication><Metabolic Processes><Metabolism><Midgut><Modern Man><Molecular><Molecular Interaction><Mosquito Control><Mosquito-borne disease><Mosquito-borne infectious disease><Mosquitoes><Mutated in Multiple Advanced Cancers 1><Nutrient><Nutritional Requirements><Oocysts><P falciparum><P. falciparum><P.falciparum><PHTS gene><PHTS protein><PTEN><PTEN gene><PTEN protein><PTEN1><Paludism><Pantothenate kinase><Pantothenic Acid><Parasite resistance><Parasitemia><Parasites><Parasitic infection><Pathway interactions><Pb element><Pediatric Hospitals><Pharmaceutical Preparations><Pharmacotherapy><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Plasmodium><Plasmodium Infections><Plasmodium falciparum><Plasmodium yoelii><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Protein Kinase><RNA Interference><RNA Silencing><RNAi><Reproduction><Research Resources><Resistance><Resistance development><Resistant development><Resources><S-acetate Coenzyme A><Saint Jude><Saint Jude Children's Cancer Center><Saint Jude Children's Research Hospital><Sequence-Specific Posttranscriptional Gene Silencing><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><St. Jude><St. Jude Children's Cancer Center><St. Jude Children's Research Hospital><St. Jude Children's Research Hospital Comprehensive Cancer Center><St.Jude Children's Cancer Center><St.Jude Children's Research Hospital><St.Jude Children's Research Hospital Comprehensive Cancer Center><Starvation><Stress><Testing><Tissue Growth><Transgenic Organisms><Validation><Vectoral capacity><Vectorial capacity><Vitamins><Work><analog><biological adaptation to stress><biological signal transduction><biological systems><biosynthesis><cofactor><developing resistance><developmental><drug modification><drug resistant><drug treatment><drug/agent><fitness><fruit fly><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><glycogen synthase a kinase><heavy metal Pb><heavy metal lead><human disease><humanized mice><humanized mouse><hydroxyalkyl protein kinase><insecticide resistant><insight><kinase inhibitor><knock-down><knockdown><life history><life span><lifespan><mouse model><murine model><mutated in multiple advanced cancers 1 protein><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><nutrient requirement><ontogeny><overexpress><overexpression><pantothenate><parasaetemia><parasite infection><parasite resistant><pathway><phosphatase and tensin homologue on chromosome ten><phosphorylase b kinase kinase><prevent><preventing><reaction; crisis><resistance to Drug><resistance to Parasite><resistant><resistant P falciparum><resistant P. falciparum><resistant Plasmodium falciparum><resistant parasite><resistant to Drug><resistant to Parasite><screening><screenings><small molecule><stress response><stress; reaction><success><tool><trait><transgenic><uptake><validations><vector mosquito>