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Principal Investigator: Silvia N Moreno
Organization: UNIVERSITY OF GEORGIA
Fiscal Year: 2024
Award: $431,149
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Apicomplexan parasites cause persistent mortality and morbidity worldwide through diseases including
malaria, toxoplasmosis, and cryptosporidiosis. The phylum member Toxoplasma gondii alone infects
approximately one third of the world population. T. gondii is an opportunistic pathogen that causes serious
disease in immunocompromised patients. Most human infections are asymptomatic but immunosuppression
due to organ transplant, cancer chemotherapy, or infection with HIV can lead to re-activation of the infection.
In addition, infection of the fetus during pregnancy causes congenital toxoplasmosis. Some exotic strains of T.
gondii have been described in tropical countries that cause severe ocular disease in immunocompetent
patients. Treatment for toxoplasmosis is challenged by lack of effective drugs to eradicate the chronic infection
and as many as one-third of AIDS patients do not respond to the therapy. Most of the drugs currently used are
poorly distributed to the central nervous system and they trigger allergic reactions in a large number of patients.
There is a compelling need for safe and effective treatments for toxoplasmosis.
The mitochondrion of T. gondii and of other apicomplexan parasites is critical for replication and several
major antiparasitic drugs, such as atovaquone and endochin-like quinolones, act through inhibition of the
mitochondrial electron transport chain at the coenzyme Q:cytochrome c reductase. The coenzyme Q (UQ)
molecule consists of a water soluble quinone head (para-hydroxybenzoate or PHBA) that can accept or donate
two electrons and a lipophilic isoprenoid tail that confines the UQ to membranes. Synthesis of the PHBA moiety
in plants and yeast occurs through the shikimate pathway, but how it is synthesized in apicomplexan is not
known. The isoprenoid unit derives from a common precursor, isopentenyl pyrophosphate (IPP), and its
isomer, dimethylallyl pyrophosphate (DMAPP), which are synthesized in mammalian cells via the mevalonate
pathway, but in T. gondii instead is synthesized via an apicoplast localized methylerythritol phosphate (MEP)
pathway. IPP and DMAPP are condensed by the action of a unique farnesyl diphosphate synthase (TgFPPS)
into farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP). Work from our laboratory
demonstrated that T. gondii is able to salvage GGPP and FPP from the host and therefore intracellular
parasites are vulnerable to inhibition of the host isoprenoid synthesis pathway. In this project we propose to
investigate the synthesis of UQ (downstream to the salvage point) and validate the pathway as a novel target.
Our preliminary data demonstrates the essentiality of three enzymatic steps and the inhibition of one of them
by a novel compound. Our hypothesis is that the synthesis of UQ represents a unique and essential pathway
with enzymatic steps liable to inhibition by specific compounds, some already in use in the clinics and potential
new ones to be discovered. We predict that exploring this pathway will reveal unique and essential enzymes
that could be targeted for improved chemotherapy against T. gondii and other apicomplexan parasites.
Terms: <AIDS><AIDS Virus><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Allergic Reaction><Anabolism><Antiparasitic Agents><Antiparasitic Drugs><Antiparasitics><Atovoquone><Bisphosphonates><Body Tissues><Bone Diseases><CNS Nervous System><Cell Body><Cells><Central Nervous System><Chemicals><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy-Oncologic Procedure><Chronic><Clinic><Clinical><CoQ6><Coenzyme Q><Coenzyme Q-Cytochrome-c Reductase><Coenzyme QH2-Cytochrome-c Reductase><Combination Chemotherapy Regimen><Complex III><Congenital Toxoplasma Infections><Congenital Toxoplasma gondii Infection><Congenital Toxoplasmosis><Country><Cryptosporidiosis><Cryptosporidium infection><Cyst><Cytochrome b-c2 Oxidoreductase><Data><Dihydroubiquinone-Cytochrome-c Reductase><Diphosphates><Disease><Disorder><Drug Kinetics><Drug Targeting><Drug usage><Drugs><Electron Transport><Electron Transport Complex III><Electrons><Enzyme Gene><Enzymes><Eye diseases><FPP synthetase><Farnesyl diphosphate synthetase><Fetus><Future><GGPP diphosphate><Generalized Growth><Genetic><Geranyltranstransferase><Gestation><Grafting Procedure><Growth><HIV><Head><Human><Human Immunodeficiency Viruses><Hydrogen Oxide><Hypercholesteremia><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Infection><Isomerism><Ketoquinolines><LAV-HTLV-III><Laboratories><Lymphadenopathy-Associated Virus><Lytotoxicity><Malaria><Mammalian Cell><Medication><Membrane><Mepron><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Negative Beta Particle><Negatrons><Neuraxis><Organ Transplantation><Organ Transplants><Outcome><Oxoquinolines><Paludism><Parasites><Parasiticides><Pathogenesis><Pathway interactions><Patients><Persons><Pharmaceutical Preparations><Pharmacokinetics><Phenotype><Phosphates><Plants><Plasmodium Infections><Population><Pregnancy><Property><Pyrophosphates><QH(2)-Cytochrome-c Reductase><QH(2)-Ferricytochrome-c Oxidoreductase><Quimioterapia><Quinolinones><Quinolones><Quinone Compound><Quinones><Research><Resistance><Supplementation><T gondii><T gondii infection><T. gondii><T. gondii infection><Tail><Techniques><Testing><Therapeutic><Tissue Growth><Tissues><Toxoplasma gondii><Toxoplasma gondii Infection><Toxoplasmosis><Treatment Failure><Ubihydroquinone-Cytochrome-c Reductase><Ubiquinol-Cytochrome-c Reductase><Ubiquinol-ferricytochrome-c oxidoreductase><Ubiquinone><Ubiquinone-Cytochrome b-c2 Oxidoreductase><Validation><Virus-HIV><Water><Wellvone><Work><Yeasts><acute infection><atovaquone><biosynthesis><biphosphonate><bisphosphonate><bone disorder><cancer chemotherapy><chemical library><chemotherapy><chronic infection><coenzyme Q6><cytotoxicity><diphosphonate><drug action><drug use><drug/agent><effective therapy><effective treatment><electron transfer><experience><eye disorder><farnesyl diphosphate><farnesyl diphosphate synthase><farnesyl pyrophosphate><farnesyl pyrophosphate synthetase><farnesylpyrophosphate><fosfidomycin><fosmidomycin><gene complementation><geranylgeranyl diphosphate><geranyltransferase><high blood cholesterol><hydroxybenzoate><hypercholesterolemia><immune competent><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressed patient><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><infected with Cryptosporidium><inhibitor><inorganic phosphate><isomer><isopentenyl diphosphate><isopentenyl pyrophosphate><isoprenoid><knock-down><knockdown><lipophilicity><member><membrane structure><mevalonate><mitochondrial><mortality><mouse model><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ocular disease><ocular disorder><ontogeny><ophthalmopathy><opportunistic pathogen><organ allograft><organ graft><organ xenograft><pathway><persistent infection><pharmacologic><resistant><shikimate><small molecule libraries><therapeutic target><therapy failure><tool><ubiquinone 6><validations>