Antiparasitic Chemotherapy: From Genomes to Mechanisms

Horn, David; Duraisingh, Manoj T.

doi:10.1146/annurev-pharmtox-011613-135915

Cited by 54 publications

(35 citation statements)

References 157 publications

(166 reference statements)

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“…Despite the advances in understanding the biology of both parasites that led to the identification of several potential biochemical targets, no new drugs have entered the clinical practice [8]. Research on new prospective drugs against HAT has only led in recent years to the delivery of a relatively safe nifurtimox-eflornithine combination therapy, the development of pentamidine-like prodrugs and the entry into clinical trials of two oral drug candidates, fexinidazole and an oxaborole [9]. Certain antifungal triazoles and protease inhibitors have shown potential in experimental models of infection with T.…”

Section: Introductionmentioning

confidence: 99%

Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites

Fernández

Arce

Sarniguet

et al. 2015

Journal of Inorganic Biochemistry

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Searching for new prospective antitrypanosomal agents, three novel Ru(II)-cyclopentadienyl compounds, [Ru(η(5)-C5H5)(PPh3)L], with HL=bioactive 5-nitrofuryl containing thiosemicarbazones were synthesized and characterized in the solid state and in solution. The compounds were evaluated in vitro on the blood circulating trypomastigote form of Trypanosoma cruzi (Dm28c strain), the infective form of Trypanosoma brucei brucei (strain 427) and on J774 murine macrophages and human-derived EA.hy926 endothelial cells. The compounds were active against both parasites with IC50 values in the micromolar or submicromolar range. Interestingly, they are much more active on T. cruzi than previously developed Ru(II) classical and organometallic compounds with the same bioactive ligands. The new compounds showed moderate to very good selectivity towards the parasites in respect to mammalian cells. The global results point at [RuCp(PPh3)L2] (L2=N-methyl derivative of 5-nitrofuryl containing thiosemicarbazone and Cp=cyclopentadienyl) as the most promising compound for further developments (IC50T. cruzi=0.41μM; IC50T. brucei brucei=3.5μM). Moreover, this compound shows excellent selectivity towards T. cruzi (SI>49) and good selectivity towards T. brucei brucei (SI>6). In order to get insight into the mechanism of antiparasitic action, the intracellular free radical production capacity of the new compounds was assessed by ESR. DMPO (5,5-dimethyl-1-pirroline-N-oxide) spin adducts related to the bioreduction of the complexes and to redox cycling processes were characterized. In addition, DNA competitive binding studies with ethidium bromide by fluorescence measurements showed that the compounds interact with this biomolecule.

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Section: Introductionmentioning

confidence: 99%

Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites

Fernández

Arce

Sarniguet

et al. 2015

Journal of Inorganic Biochemistry

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“…Next-generation sequencing (NGS) technologies have enabled the high-throughput and genome-scale screening of eukaryotic pathogens, and have been useful in identifying drug targets and elucidating drug resistance mechanisms (4,5). The development of RNA interference (RNAi) target sequencing (RIT-Seq) in kinetoplastid parasites, such as Trypanosoma brucei (6), has revealed numerous genes associated with drug action (7); however, RNAibased screening is not applicable to Leishmania, because most species lack functional RNAi machinery (8).…”

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confidence: 99%

Cos-Seq for high-throughput identification of drug target and resistance mechanisms in the protozoan parasite Leishmania

Gazanion

Fernández-Prada

Papadopoulou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

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Innovative strategies are needed to accelerate the identification of antimicrobial drug targets and resistance mechanisms. Here we develop a sensitive method, which we term Cosmid Sequencing (or "Cos-Seq"), based on functional cloning coupled to next-generation sequencing. Cos-Seq identified >60 loci in the Leishmania genome that were enriched via drug selection with methotrexate and five major antileishmanials (antimony, miltefosine, paromomycin, amphotericin B, and pentamidine). Functional validation highlighted both known and previously unidentified drug targets and resistance genes, including novel roles for phosphatases in resistance to methotrexate and antimony, for ergosterol and phospholipid metabolism genes in resistance to miltefosine, and for hypothetical proteins in resistance to paromomycin, amphothericin B, and pentamidine. Several genes/loci were also found to confer resistance to two or more antileishmanials. This screening method will expedite the discovery of drug targets and resistance mechanisms and is easily adaptable to other microorganisms.

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“…Inhibition of metabolic processes essential to microorganisms is a fruitful strategy for the development of effective drugs (11). Several widely used drugs target the metabolism of the pathogen to exert their killing effect, such as the antimalarials atovaquone and proguanil, and the broad-spectrum antihelminthic and antiprotozoal nitazoxanide (12, 13).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of fatty acid oxidation as a new target to treat Primary Amoebic Meningoencephalitis by repurposing two well-known drugs

Sarink

Verbon

Tielens

et al. 2019

Preprint

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14Primary Amoebic Meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-15 living amoeba Naegleria fowleri. The disease mostly affects healthy children and young 16 adults after contaminated water enters the nose, generally during recreational water activities. 17 The amoeba migrate along the olfactory nerve to the brain, resulting in seizures, coma and 18 eventually death. Previous research has shown that Naegleria gruberi, a close relative of N. 19 fowleri, prefers lipids over glucose as an energy source. Therefore, we tested several 20 inhibitors of fatty acid oxidation alongside the currently used drugs amphotericin B and 21 miltefosine. Our data demonstrate that etomoxir, orlistat, perhexiline, thioridazine and 22 valproic acid inhibited growth of N. gruberi. Furthermore, additive effects were seen when 23 drugs were combined. Both thioridazine and valproic acid inhibit in vitro growth of N. 24 gruberi in concentrations that can be obtained at the site of infection, which is doubtful with 25 the currently used drugs amphotericin B and miltefosine. Both thioridazine and valproic acid 26 have already been used for other diseases. As the development of new drugs and randomized 27 controlled trials for this rare disease is nearly impossible, repurposing drugs is the most 28 promising way to obtain additional drugs to combat PAM. Thioridazine and valproic acid are 29 available drugs without major side-effects and can, therefore, be used as new complementary 30 options in PAM therapy. 31 49 the pathogen to exert their killing effect, such as the antimalarials atovaquone and proguanil, 50 and the broad-spectrum antihelminthic and antiprotozoal nitazoxanide (12, 13). 51Previous research by our group showed that N. gruberi, a close relative to N. fowleri, 52 prefers fatty acids as a food source (14). This led us to the hypothesis that inhibiting fatty acid 53 oxidation (FAO) could inhibit growth or even kill the amoeba. We identified several drugs 54 that inhibit fatty acid metabolism in different parts of this pathway. As the metabolic 55 machinery of N. gruberi is highly similar to that of N. fowleri (14-16), we used N. gruberi as a 56 4 model organism to determine the effects of these compounds. We then compared the effects 57 of these inhibitors to the currently used treatment (AMB and MIL) and determined additive 58 effects of the compounds when they were combined. 59 60 Materials and Methods 61 Chemicals and amoeba culture. N. gruberi strain NEG-M (ATCC® 30224) was grown 62 axenically at 25 ˚C in modified PYNFH medium (ATCC medium 1034), as described before 63 (14). Modified PYNFH is composed of peptone, yeast extract, yeast nucleic acid, folic acid, 64 10% heat-inactivated fetal bovine serum, 100 units/ml penicillin, 100 µg/ml streptomycin and 65 40 µg/ml gentamicin. All experiments were performed using trophozoites harvested during 66 the logarithmic phase of growth. Amphotericin B (AMB), etomoxir (ETO), miltefosine 67 (MIL), thioridazine (TDZ), orlistat (ORL), perhexiline (PHX...

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Antiparasitic Chemotherapy: From Genomes to Mechanisms

Cited by 54 publications

References 157 publications

Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites

Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites

Cos-Seq for high-throughput identification of drug target and resistance mechanisms in the protozoan parasite Leishmania

Inhibition of fatty acid oxidation as a new target to treat Primary Amoebic Meningoencephalitis by repurposing two well-known drugs

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