Kathy Andrews

Erratum to Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites [Int. J. Parasitol. Drugs Drug Res. 5 (2015) 117-126].

Publisher: Elsevier BV

Date: 12-2016

DOI: 10.1016/J.IJPDDR.2016.05.001

Characterization of VAR2CSA-deficient Plasmodium falciparum-infected erythrocytes selected for adhesion to the BeWo placental cell line

Publisher: Springer Science and Business Media LLC

Date: 26-03-2008

DOI: 10.1186/1475-2875-7-51

Abstract: Malaria in pregnancy is characterized by accumulation of infected erythrocytes (IE) in the placenta. The key ligand identified as mediating this process is a Plasmodium falciparum erythrocyte membrane protein 1 family member, termed VAR2CSA. VAR2CSA appears to be the main ligand responsible for adhesion to chondroitin sulphate A (CSA). Whether other PfEMP1 molecules can also mediate placental adhesion, independent of CSA binding, is unclear. The parasite line CS2 carrying a disrupted var2csa gene (CS2KO) was selected for adhesion to the BeWo choriocarcinoma cell line, which has been proposed as a model for placental malaria. The selected and control IE were tested for adhesion to placental sections and flow cytometry was used to measure recognition of IE by three serum sets from malaria-exposed men and women. Wild-type CS2 adhere to BeWo and placental tissue via CSA. CS2KO IE were successfully selected for adhesion to BeWo, and adhered by a CSA-independent mechanism. They bound to immobilized ICAM-1 and CD36. BeWo-selected CS2KO bound at moderate levels to placental sections, but most binding was to placental villi rather than to the syncytiotrophoblast to which IE adherence occurs in vivo . This binding was inhibited by a blocking antibody to CD36 but not to ICAM-1. As expected, sera from malaria-exposed adults recognized CS2 IE in a gender and parity dependent manner. In one serum set, there was a similar but less pronounced pattern of antibody binding to selected CS2KO IE, but this was not seen in two others. One var gene, It4 var19 , was particularly abundant in the selected line and was detected as full length transcripts in BeWo-selected IE, but not unselected CS2KO. This study suggests that IE with characteristics similar to the CS2KO have a limited role in the pathogenesis of placental malaria. VAR2CSA appear to be the major ligand for placental adhesion, and could be the basis for a vaccine against pregnancy malaria.

Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites

Publisher: Elsevier BV

Date: 12-2015

DOI: 10.1016/J.IJPDDR.2015.05.004

Plasmodium Gametocyte Inhibition Identified from a Natural-Product-Based Fragment Library

Publisher: American Chemical Society (ACS)

Date: 03-10-2013

DOI: 10.1021/CB400582B

Abstract: Fragment-based screening is commonly used to identify compounds with relatively weak but efficient localized binding to protein surfaces. We used mass spectrometry to study fragment-sized three-dimensional natural products. We identified seven securinine-related compounds binding to Plasmodium falciparum 2'-deoxyuridine 5'-triphosphate nucleotidohydrolase (PfdUTPase). Securinine bound allosterically to PfdUTPase, enhancing enzyme activity and inhibiting viability of both P. falciparum gametocyte (sexual) and blood (asexual) stage parasites. Our results provide a new insight into mechanisms that may be applicable to transmission-blocking agents.

Plasmodium falciparum: new molecular targets with potential for antimalarial drug development

Publisher: Informa UK Limited

Date: 11-2009

DOI: 10.1586/ERI.09.93

Abstract: Malaria remains one of the world's most devastating infectious diseases. Drug resistance to all classes of antimalarial agents has now been observed, highlighting the need for new agents that act against novel parasite targets. The complete sequencing of the Plasmodium falciparum genome has allowed the identification of new molecular targets within the parasite that may be amenable to chemotherapeutic intervention. In this review, we investigate four possible targets for the future development of new classes of antimalarial agents. These targets include histone deacetylase, the aspartic proteases or plasmepsins, aminopeptidases and the purine salvage enzyme hypoxanthine-xanthine-guanine phosphoribosyltransferase.

The histone H4 gene of Plasmodium falciparum is developmentally transcribed in asexual parasites

Publisher: Springer Science and Business Media LLC

Date: 08-2003

DOI: 10.1007/S00436-003-0874-X

Abstract: Histones are abundant nuclear core proteins that are present in all eukararyotes and are responsible for linking chromosomes and packaging them into tight chromatin aggregates. The histone H2A, H2B, and H3 genes and a partial sequence of the histone H4 gene from Plasmodium falciparum have been previously identified and share a high level of nucleotide sequence identity. In this study, we compare the histone H4 sequence of the human malaria P. falciparum with the sequences of two mouse malarias, Plasmodium berghei and Plasmodium yoelii, revealing at least 91% identity at the nucleotide level and 100% conservation at the amino acid level. Furthermore, we show the P. falciparum histone H4 is developmentally transcribed in late stage asexual parasites, completing the transcription profile for the genes comprising the histone octamer of P. falciparum and adding support to suggestions that a novel histone mRNA control mechanism exists in this parasite.

A Sesquiterpene Isonitrile with a New Tricyclic Skeleton from the Indo-Pacific Nudibranch Phyllidiella pustulosa: Spectroscopic and Computational Studies

Publisher: CSIRO Publishing

Date: 2020

DOI: 10.1071/CH19227

Abstract: The sesquiterpene isonitrile, 9-isocyanoneoallopupukeanane 1, has been obtained from the Indo-Pacific nudibranch Phyllidiella pustulosa. The structure of 1, which was investigated by extensive NMR experiments, molecular modelling studies, and density functional calculations, has a different arrangement of the tricyclic ring system compared with other isonitrile metabolites isolated from nudibranchs or sponges. The viability of a biosynthetic pathway leading to 1, proposed to involve a series of carbocation rearrangements, is explored in a computational study. Isonitrile 1 exhibited micromolar antimalarial activity when screened against Plasmodium falciparum infected erythrocytes.

Reevaluating the classification ofHalobacteroidesandHaloanaerobacterspecies based on sequence comparisons of the 16S ribosomal RNA gene

Publisher: Oxford University Press (OUP)

Date: 12-1995

DOI: 10.1111/J.1574-6968.1995.TB07924.X

Abstract: The 16S rRNA gene (rDNA) sequence analysis of four halophilic anaerobes: Halobacteroides halobius, H. lacunaris. Haloanaerobacter (Hb.) chitinovorans and H. acetoethylicus confirmed that they were all members of the family Haloanaerobiaceae. H. lacunaris and H. halobius were found to be more closely related to each other and were distantly related to Sporohalobacter lortetti and the members of the genera Haloanaerobium and Halothermothrix. These data are in agreement with their assignment to the genus Halobacteroides. Further analysis indicated that Hb. chitinovorans was closely affiliated to members of the genus Halobacteroides, and therefore we propose to transfer it to the genus Halobacteroides as H. chitinovorans comb. nov. This transfer would invalidate the genus Haloanaerobacter, as Hb. chitinovorans is the only member of this genus. The 16S rDNA sequence analysis of H. acetoethylicum indicated that it was very closely related to members of the genus Haloanaerobium, viz. Haloanaerobium (Ha.) praevalens, Ha. salsugo, and Ha. alcaliphilum, and hence we propose to transfer it to the genus Haloanaerobium as Ha. acetoethylicus comb. nov.

Engaging rural Australian communities in National Science Week helps increase visibility for women researchers

Publisher: The Royal Society

Date: 10-2017

DOI: 10.1098/RSOS.170548

Abstract: During a week-long celebration of science, run under the federally supported National Science Week umbrella, the Catch a Rising Star: women in Queensland research (CaRS) programme flew scientists who identify as women to nine regional and remote communities in the Australian State of Queensland. The aim of the project was twofold: first, to bring science to remote and regional communities in a large, economically erse state and second, to determine whether media and public engagement provides career advancement opportunities for women scientists. This paper focuses on the latter goal. The data show: (i) a substantial majority (greater than 80%) of researchers thought the training and experience provided by the programme would help develop her career as a research scientist in the future, (ii) the majority (65%) thought the programme would help relate her research to end users, industry partners or stakeholders in the future, and (iii) analytics can help create a compelling narrative around engagement metrics and help to quantify influence. During the week-long project, scientists reached 600 000 impressions on one social media platform (Twitter) using a program hashtag. The breadth and depth of the project outcomes indicate funding bodies and employers could use similar data as an informative source of metrics to support hiring and promotion decisions. Although this project focused on researchers who identify as women, the lessons learned are applicable to researchers representing a erse range of backgrounds. Future surveys will help determine whether the CaRS programme provided long-term career advantages to participating scientists and communities.

Design and synthesis of screening libraries based on the muurolane natural product scaffold

Publisher: Royal Society of Chemistry (RSC)

Date: 2012

DOI: 10.1039/C2OB00029F

Abstract: The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chemically elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritised based on drug-like physicochemical parameters such as log P, log D(5.5), hydrogen bond donors/acceptors, and molecular weight. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchellii and then utilised in the parallel solution-phase generation of two series of analogues. The first library consisted of six semi-synthetic amide derivatives, whilst the second contained six carbamate analogues. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compounds displayed low to moderate activity with IC(50) values ranging from 14 to 33 μM.

Sulfonamide inhibition studies of the η-class carbonic anhydrase from the malaria pathogen Plasmodium falciparum

Publisher: Elsevier BV

Date: 02-2015

DOI: 10.1016/J.BMC.2014.12.009

Abstract: The η-carbonic anhydrases (CAs, EC 4.2.1.1) were recently discovered as the sixth genetic class of this metalloenzyme superfamily, and are so far known only in protozoa, including various Plasmodium species, the causative agents of malaria. We report here an inhibition study of the η-CA from Plasmodium falciparum (PfCA) against a panel of sulfonamides and one sulfamate compound, some of which are clinically used. The strongest inhibitors identified were ethoxzolamide and sulthiame, with KIs of 131-132 nM, followed by acetazolamide, methazolamide and hydrochlorothiazide (KIs of 153-198 nM). Brinzolamide, topiramate, zonisamide, indisulam, valdecoxib and celecoxib also showed significant inhibitory action against PfCA, with KIs ranging from 217 to 308 nM. An interesting observation was that the more efficient PfCA inhibitors are representative of several scaffolds and chemical classes, including benzene sulfonamides, monocyclic/bicyclic heterocyclic sulfonamides and compounds with a more complex scaffold (i.e., the sugar sulfamate derivative, topiramate, and the coxibs, celecoxib and valdecoxib). A comprehensive inhibition study of small molecules for η-CAs is needed as a first step towards assessing PfCA as a druggable target. The present work identifies the first known η-CA inhibitors and provides a platform for the development of next generation novel PfCA inhibitors.

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Publisher: American Society for Microbiology

Date: 07-2014

DOI: 10.1128/AAC.02721-13

Abstract: Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in Plasmodium falciparum gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in P. falciparum gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology.

Synthesis and Antiplasmodial Evaluation of Analogues Based on the Tricyclic Core of Thiaplakortones A-D.

Publisher: MDPI AG

Date: 15-09-2015

DOI: 10.3390/MD13095784

QSAR Classification Models for Prediction of Hydroxamate Histone Deacetylase Inhibitor Activity against Malaria Parasites

Publisher: American Chemical Society (ACS)

Date: 05-01-2022

DOI: 10.1021/ACSINFECDIS.1C00355

Abstract: Malaria, caused by

Discovery of 1,3,4-oxadiazoles with slow-action activity againstPlasmodium falciparummalaria parasites

Publisher: Cold Spring Harbor Laboratory

Date: 10-03-2023

DOI: 10.1101/2023.03.09.531229

Abstract: To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum . This work identified N , N -dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplas-modial chemotype (e.g., 1 96 h IC 50 550 nM) with a different action to delayed-death slow-action drugs. Structure activity relationship analysis of analogues identified multiple compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC 50 nM SI ,500). However subsequent studies in mice with lead compound 1 , which had the best microsomal stability of the compounds assessed, demonstrated rapid clearance (T 1/2 1.6 h) and poor oral in vivo efficacy. This indicates that improvements in the pharmacokinetic profile of N , N -dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines would be needed for the development of this chemotype for malaria chemoprophylaxis.

β-lactam antibiotic versus combined β-lactam antibiotics and single daily dosing regimens of aminoglycosides for treating serious infections: A meta-analysis

Publisher: Elsevier BV

Date: 03-2020

DOI: 10.1016/J.IJANTIMICAG.2019.10.020

Abstract: Combining aminoglycosides with β-lactam antibiotics for treating serious infections has not been associated with reduced mortality in previous meta-analyses. However, the multiple daily aminoglycoside dosing regimen principally used in most of the included studies is inconsistent with current practice. To determine if a combination of an aminoglycoside administered as a single daily dose and a β-lactam antibiotic reduces all-cause mortality in patients compared with β-lactam antibiotic monotherapy. A systematic review and meta-analysis of clinical studies was performed (Prospero registration number #68506). Studies were included if they compared β-lactam antibiotic monotherapy with combined β-lactam and single daily dose aminoglycoside therapy for treating serious infections. Studies investigating multiple daily dosing aminoglycoside regimens, infective endocarditis and febrile neutropaenia were excluded. Study quality was assessed using the PEDro and Newcastle-Ottawa scoring systems. The end points for outcome analyses were 30-day all-cause mortality, clinical cure and nephrotoxicity. Four randomised controlled trials and five retrospective cohort studies were analysed. Compared with β-lactam antibiotic monotherapy, single daily aminoglycoside dosing in combination with β-lactam antibiotics was not associated with reduced mortality compared with β-lactam antibiotic monotherapy (n = 3686, OR 0.82, 95% CI 0.63-1.08, P = 0.10, I The existing evidence suggests no added survival benefit from a single daily dosing regimen of an aminoglycoside when combined with β-lactam antibiotics.

Psammaplysin derivatives from the Balinese marine sponge Aplysinella strongylata.

Publisher: American Chemical Society (ACS)

Date: 06-12-2012

DOI: 10.1021/NP300560B

Abstract: Twenty-one new psammaplysin derivatives (4-24) exhibiting a variety of side chains, as well as six previously known psammaplysins, were identified from the Indonesian marine sponge Aplysinella strongylata. The double bond on the side chain of the fatty acid-containing psammaplysins was located by GC-MS analysis of the fatty acid methyl esters and their pyrrolidide derivatives. HPLC and Mosher ester studies confirmed that the isolated metabolites possessing a 19-OH substituent were mixtures of diastereomers. Selected compounds (4, 5, 7, 8, 12, 18, and 22) were screened for in vitro activity against chloroquine-sensitive (3D7) P. falciparum malaria parasites. Of the new psammaplysins, 19-hydroxypsammaplysin E (4) showed the best antimalarial activity, with an IC(50) value of 6.4 μM.

Antiparasitic activity of alkaloids from plant species of Papua New Guinea and Australia

Publisher: Elsevier BV

Date: 09-2010

DOI: 10.1016/J.IJANTIMICAG.2010.05.008

Abstract: New drugs are needed to help overcome the increasing problem of drug resistance in parasites that cause diseases such as malaria and trypanosomiasis. In this study, alkaloid compounds isolated from extracts of the plants Flindersia amboinensis, Stephania zippeliana and Voacanga papuana from Papua New Guinea and Flindersia acuminata from Australia were examined for their antiparasitic activity against Plasmodium falciparum strains and Trypanosoma brucei brucei as well as their cytotoxicity against the mammalian cell lines HEK 293 and HeLa. The most active compound, dimethylisoborreverine (DMIB), showed submicromolar activity, with 50% inhibitory concentration (IC(50)) values between 20 nM and 810 nM both against drug-sensitive and drug-resistant P. falciparum strains, along with moderate selectivity against T. b. brucei and mammalian cells. Stage specificity studies revealed that P. falciparum trophozoite-stage parasites were more susceptible to DMIB than ring- or schizont-stage parasites. DMIB-treated trophozoites showed changes in food vacuole morphology, with an apparent reduction in haemozoin formation that does not appear to be inhibited via the direct binding of haem. These findings suggest a potential for indole alkaloids from Flindersia spp. as new antiparasitic agents.

Evaluation of the role of the endocytic receptor L-SIGN for cytoadhesion of Plasmodium falciparum-infected erythrocytes

Publisher: Springer Science and Business Media LLC

Date: 04-05-2005

DOI: 10.1007/S00436-005-1360-4

Abstract: Hepatic cell populations play an important role during the malaria life cycle. L-SIGN, a homologue of DC-SIGN, mediating leukocyte and pathogen binding, is selectively expressed on liver endothelial cells. Here, we present evidence that L-SIGN acts as an endocytic cell surface receptor. However, P. falciparum-infected erythrocytes did not cytoadhere to L-SIGN. Thus, L-SIGN contributes to elimination of mannosylated ligands but does not participate in hepatic clearance of P. falciparum-infected erythrocytes.

Maternal malaria: Plasmodium falciparum sequestration in the placenta

Publisher: Springer Science and Business Media LLC

Date: 08-2002

DOI: 10.1007/S00436-002-0624-5

Abstract: The human malarial parasite Plasmodium falciparumis responsible for an estimated 300-500 million clinical cases and 1-3 million deaths annually. At particular risk of developing severe, life-threatening malaria-associated complications are women during their first pregnancy. The observed pathologies, such as premature delivery, intrauterine growth retardation, abortion, and death of the mother and the newborn, are in large parts due to the parasite's ability to render infected erythrocytes adhesive and sequester in the intervillous space of infected placentas. In subsequent pregnancies, women are protected from maternal malaria through antibodies that prevent cytoadhesion of P. falciparum-infected erythrocytes in the placenta. Here, we summarize our current knowledge of the pathophysiological processes underpinning maternal malaria and discuss emerging concepts for intervention.

Investigation of the in vitro and in vivo efficacy of peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity

Publisher: Elsevier BV

Date: 02-2021

DOI: 10.1016/J.EJMECH.2020.113065

Activity of bromodomain protein inhibitors/binders against asexual-stage Plasmodium falciparum parasites.

Publisher: Elsevier BV

Date: 08-2018

DOI: 10.1016/J.IJPDDR.2018.03.001

Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

Publisher: Wiley

Date: 07-07-2017

DOI: 10.1096/FJ.201700288R

Catalyst-Controlled Stereoselective Synthesis Secures the Structure of the Antimalarial Isocyanoterpene Pustulosaisonitrile-1

Publisher: American Chemical Society (ACS)

Date: 28-11-2017

DOI: 10.1021/ACS.JOC.7B02421

Abstract: Three new isocyanoditerpenes (5-7) have been characterized from Australian specimens of the nudibranch Phyllidiella pustulosa. The planar structure and (3R,6S,7R) absolute configuration of pustulosaisonitrile-1 were deduced by spectroscopic analyses at 900 MHz informed by molecular modeling, DFT calculations, and computational NMR chemical shift predictions and by comparison of experimental electronic circular dichroism (ECD) data with TDDFT-ECD calculations for the truncated model compound 8. A catalyst-controlled enantio- and diastereoselective total synthesis of the two most likely diastereomeric candidates for the structure of 5 solidified its (3R,6S,7R,10S,11R,14R) absolute configuration. Three in idual enantioselective methods provided stereochemical control at key positions, permitting an unambiguous final structural assignment. Isocyanide 5 and synthetic diastereomers 5a and 5c showed activity against Plasmodium falciparum malaria parasites (IC

Antimalarial Activity of Phenylthiazolyl-Bearing Hydroxamate-Based Histone Deacetylase Inhibitors

Publisher: American Society for Microbiology

Date: 10-2008

DOI: 10.1128/AAC.00439-08

Abstract: The antimalarial activity and pharmacology of a series of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors (HDACIs) was evaluated. In in vitro growth inhibition assays approximately 50 analogs were evaluated against four drug resistant strains of Plasmodium falciparum . The range of 50% inhibitory concentrations (IC 50 s) was 0.0005 to μM. Five analogs exhibited IC 50 s of nM, and three of these exhibited selectivity indices of . The most potent compound, WR301801 (YC-2-88) was shown to cause hyperacetylation of P. falciparum histones, which is a marker for HDAC inhibition in eukaryotic cells. The compound also inhibited malarial and mammalian HDAC activity in functional assays at low nanomolar concentrations. WR301801 did not exhibit cures in P. berghei -infected mice at oral doses as high as 640 mg/kg/day for 3 days or in P. falciparum -infected Aotus lemurinus lemurinus monkeys at oral doses of 32 mg/kg/day for 3 days, despite high relative bioavailability. The failure of monotherapy in mice may be due to a short half-life, since the compound was rapidly hydrolyzed to an inactive acid metabolite by loss of its hydroxamate group in vitro (half-life of 11 min in mouse microsomes) and in vivo (half-life in mice of 3.5 h after a single oral dose of 50 mg/kg). However, WR301801 exhibited cures in P. berghei -infected mice when combined at doses of 52 mg/kg/day orally with subcurative doses of chloroquine. Next-generation HDACIs with greater metabolic stability than WR301801 may be useful as antimalarials if combined appropriately with conventional antimalarial drugs.

The discovery, synthesis and antimalarial evaluation of natural product-based polyamine alkaloids

Publisher: Elsevier BV

Date: 09-2013

DOI: 10.1016/J.TETLET.2013.07.058

Discovery, Synthesis and Antimalarial Evaluation of Natural Product-based Polyamines

Publisher: Georg Thieme Verlag KG

Date: 04-07-2013

DOI: 10.1055/S-0033-1348550

Synthesis and antimalarial evaluation of a screening library based on a tetrahydroanthraquinone natural product scaffold

Publisher: Elsevier BV

Date: 12-2012

DOI: 10.1016/J.BMC.2012.09.052

Abstract: As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi a unique fungi-derived prefractionated library was screened against a chloroquine-sensitive Plasmodium falciparum line (3D7) using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius species displayed promising antimalarial activity. UV-guided fractionation on the CH(2)Cl(2)/MeOH extract from this fungus resulted in the isolation of four known compounds: (1S,3R)-austrocortirubin (1), (1S,3S)-austrocortirubin (2), 1-deoxyaustrocortirubin (3), and austrocortinin (4). Compound 2 was used as a natural product scaffold in the parallel solution-phase synthesis of a small library of N-substituted tetrahydroanthraquinones (5-15). All compounds (1-15) were tested in vitro against P. falciparum 3D7 parasites and (1S,3S)-austrocortirubin (2), the major fungal constituent, was shown to be the most active compound with an IC(50) of 1.9 μM. This compound displayed moderate cytotoxicity against neonatal foreskin fibroblast (NFF) cells with an IC(50) of 15.6 μM.

Rapid loss of group 1 innate lymphoid cells during blood stage Plasmodium infection

Publisher: Wiley

Date: 2018

DOI: 10.1002/CTI2.1003

Effect of cytokine treatment on the in vitro expression of the P. falciparum adhesion receptor chondroitin-4-sulphate on the surface of human choriocarcinoma (BeWo) cells

Publisher: Springer Science and Business Media LLC

Date: 16-02-2007

DOI: 10.1007/S00436-007-0473-3

Abstract: BeWo human choriocarcinoma cells have recently been identified as an in vitro model of adhesion of Plasmodium falciparum-infected erythrocytes to the major placental receptor chondroitn-4-sulphate (CSA). In this study, we show that treatment of BeWo cells with tumour necrosis factor-alpha and/or interferon-gamma, cytokines linked with pregnancy-associated malaria and poor pregnancy outcome, does not alter the expression of cell surface CSA. BeWo cells do not express the common P. falciparum adhesion receptor cluster of differentiation 36 (CD36) on the cell surface, and this was unchanged after treatment with cytokines. These data demonstrate that in vitro cultured BeWo cells mimic the P. falciparum adhesion receptor expression profile of ex vivo placental cytotrophoblast cells.

Intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by Gram-negative bacilli: A systematic review

Publisher: Elsevier BV

Date: 03-2019

DOI: 10.1016/J.IJANTIMICAG.2018.11.011

Abstract: Knowledge of antibiotic concentrations achievable in the epithelial lining fluid (ELF) will help guide antibiotic dosing for treating patients with Gram-negative bacillary ventilator-associated pneumonia (VAP). To compare: (1) the ELF:serum penetration ratio of antibiotics in patients with pneumonia, including VAP, with that in healthy study participants and (2) the ELF and/or tracheal aspirate antibiotic concentrations following intravenous and nebuliser delivery. Web of Science, EMBASE and PubMed databases were searched and a systematic review undertaken. Fifty-two studies were identified. ELF penetration ratios for aminoglycosides and most β-lactam antibiotics administered intravenously were between 0.12 and 0.57, whereas intravenous colistin may be undetectable in the ELF. In contrast, estimated mean fluoroquinolone ELF penetration ratios of up to 1.31 were achieved. Importantly, ELF penetration ratios appear reduced in critically ill patients with pneumonia compared with in healthy volunteers receiving intravenous ceftazidime, levofloxacin and fosfomycin thus, dose adjustment is likely to be required in critically ill patients. In contrast to the systemic administration route, nebulisation of antibiotics achieves high ELF concentrations. Nebulised 400 mg twice-daily amikacin resulted in a median peak ELF steady-state concentration of 976.01 mg/L (interquartile range 410.3-2563.1 mg/L). Similarly, nebulised 1 million international units of colistin resulted in a peak ELF concentration of 6.73 mg/L (interquartile range 4.80-10.10 mg/L). Further pharmacokinetic studies investigating the mechanisms for ELF penetration in infected patients and healthy controls are needed to guide antibiotic dosing in VAP and to determine the potential benefits of nebulised therapy.

Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐Plasmodium Activity

Publisher: Wiley

Date: 13-09-2017

DOI: 10.1002/CMDC.201700360

Abstract: In this work we aimed to develop parasite-selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid-based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC

Inhibition of Plasmodium falciparum growth in vitro and adhesion to chondroitin-4-sulfate by the heparan sulfate mimetic PI-88 and other sulfated oligosaccharides

Publisher: American Society for Microbiology

Date: 08-2006

DOI: 10.1128/AAC.00313-06

Abstract: A panel of sulfated oligosaccharides was tested for antimalarial activity and inhibition of adhesion to the placental malaria receptor chondroitin-4-sulfate (CSA). The heparan sulfate mimetic PI-88, currently undergoing phase II anticancer trials, displayed the greatest in vitro antimalarial activity against Plasmodium falciparum (50% inhibitory concentration of 7.4 μM) and demonstrated modest adhesion inhibition to cell surface CSA.

Structural basis for binding of Plasmodium falciparum erythrocyte membrane protein 1 to chondroitin sulfate and placental tissue and the influence of protein polymorphisms on binding specificity

Publisher: Elsevier BV

Date: 08-2007

DOI: 10.1074/JBC.M700231200

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

Publisher: American Chemical Society (ACS)

Date: 13-02-0001

DOI: 10.1021/ACSINFECDIS.7B00197

Plagiarism

Publisher: Oxford University Press (OUP)

Date: 08-2009

DOI: 10.1016/J.TRSTMH.2009.05.006

Acaricidal activity of eugenol based compounds against scabies mites

Publisher: Public Library of Science (PLoS)

Date: 11-08-2010

DOI: 10.1371/JOURNAL.PONE.0012079

Regioselectively modified sulfated cellulose as prospective drug for treatment of malaria tropica

Publisher: Springer Science and Business Media LLC

Date: 18-11-2006

DOI: 10.1007/S10719-006-9012-1

Abstract: Adhesion of Plasmodium falciparum infected erythrocytes (IE) to placental chondroitin-4-sulfate (CSA) has been linked to the severe disease outcome of pregnancy-associated malaria. Consequently, sulfated polysaccharides with inhibitory capacity may be considered for therapeutic strategies as anti-adhesive drugs. During in vitro screening a regioselectively modified cellulose sulfate (CS10) was selected as prime candidate for further investigations because it was able to inhibit adhesion to CSA expressed on CHO cells and placental tissue, to de-adhere already bound infected erythrocytes, and to bind to infected erythrocytes. Similar to the undersulfated placental CSA preferred by placental-binding infected erythrocytes, CS10 is characterized by a clustered sulfate pattern along the polymer chain. In further evaluation of its effects on P. falciparum interactions with host erythrocytes, we now show that CS10 inhibits the in vitro asexual growth of parasites in erythrocytes. Furthermore, we show that CS10 interferes with C1 of the classical complement pathway but not with MBL of the lectin pathway. In order to gain insights into the possible interactions of CS10 with known parasite receptors at the molecular level, we designed 3D-structures of characteristic stretches of CS10. CS10 fragments with clustered sulfate groups showed complex patterns of hydrophobic and hydrophilic patches most likely suitable for interactions with protein binding partners. The significance of CS10 interactions with the complement system as well as its anti-malarial effect for prospective drug application are discussed.

Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.IJPDDR.2021.08.006

The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides

Publisher: American Society for Microbiology

Date: 22-12-2020

DOI: 10.1128/MBIO.02842-20

Abstract: Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue, causing 405,000 deaths and 228 million cases in 2018. Understanding key metabolic processes in malaria parasites is critical to the development of new drugs to combat this major infectious disease. The Plasmodium glycolytic pathway is essential to the malaria parasite, providing energy for growth and replication and supplying important biomolecules for other essential Plasmodium anabolic pathways. Despite this overreliance on glycolysis, no current drugs target glycolysis, and there is a paucity of information on critical glycolysis targets. Our work addresses this unmet need, providing new mechanistic insights into this key pathway.

ASSOCIATION OF PLASMODIUM FALCIPARUM ISOLATES ENCODING THE P. FALCIPARUM CHLOROQUINE RESISTANCE TRANSPORTER GENE K76T POLYMORPHISM WITH ANEMIA AND SPLENOMEGALY, BUT NOT WITH MULTIPLE INFECTIONS

Publisher: American Society of Tropical Medicine and Hygiene

Date: 03-2005

DOI: 10.4269/AJTMH.2005.72.252

Adherence of Plasmodium falciparum infected erythrocytes to CHO-745 cells and inhibition of binding by protein A in the presence of human serum

Publisher: Elsevier BV

Date: 09-2005

DOI: 10.1016/J.IJPARA.2005.05.007

Abstract: Adhesion of erythrocytes infected with the malaria parasite Plasmodium falciparum to human host receptors is a process associated with severe malarial pathology. A number of in vitro cell lines are available as models for these adhesive processes, including Chinese hamster ovary (CHO) cells which express the placental adhesion receptor chondroitin-4-sulphate (CSA) on their surface. CHO-745 cells, a glycosaminoglycan-negative mutant CHO cell line lacking CSA and other reported P. falciparum adhesion receptors, are often used for recombinant expression of host receptors and for receptor binding studies. In this study we show that P. falciparum-infected erythrocytes can be easily selected for adhesion to an endogenous receptor on the surface of CHO-745 cells, bringing into question the validity of using these cells as a tool for P. falciparum adhesin expression studies. The adhesive interaction between CHO-745 cells and parasitized erythrocytes described here is not mediated by the known P. falciparum adhesion receptors CSA, CD36, or ICAM-1. However, we found that CHO-745-selected parasitized erythrocytes bind normal human IgM and that adhesion to CHO-745 cells is inhibited by protein A in the presence of serum, but not in its absence, indicating a non-specific inhibitory effect. Thus, protein A, which has been used as an inhibitor for a recently described interaction between infected erythrocytes and the placenta, may not be an appropriate in vitro inhibitor for understanding in vivo adhesive interactions.

Antiretrovirals as antimalarial agents

Publisher: Oxford University Press (OUP)

Date: 12-2004

DOI: 10.1086/425584

Abstract: Recent studies have indicated that antiretroviral protease inhibitors may affect outcome in malarial disease. We have investigated the antimalarial activities of 6 commonly used antiretroviral agents. Our data indicate that, in addition to the previously published effects on cytoadherence and phagocytosis, the human immunodeficiency virus (HIV)-1 protease inhibitors saquinavir, ritonavir, and indinavir directly inhibit the growth of Plasmodium falciparum in vitro at clinically relevant concentrations. These findings are particularly important in light of both the high rate of malaria and HIV-1 coinfection in sub-Saharan Africa and the effort to employ highly active antiretroviral therapy in these regions.

The activity of protease inhibitors against Giardia duodenalis and metronidazole-resistant Trichomonas vaginalis.

Publisher: Elsevier BV

Date: 2006

DOI: 10.1016/J.IJANTIMICAG.2006.08.026

Abstract: Antiretroviral protease inhibitors were assessed in vitro for their activity against Giardia duodenalis and Trichomonas vaginalis. Kaletra (a co-formulation of ritonavir and lopinavir) was the most effective overall, with 50% effective drug concentrations (EC(50)) of 1.1-2.7 microM (ritonavir concentration) against G. duodenalis and 6.8-8 microM against metronidazole-sensitive and clinically metronidazole-resistant T. vaginalis. Minimal inhibitory concentrations were 2-2.5 microM and 10-50 microM for G. duodenalis and T. vaginalis, respectively. Within the range of human plasma concentrations for ritonavir, only G. duodenalis was inhibited. Lopinavir alone was less inhibitory than ritonavir but was associated with a blockage in cytokinesis of G. duodenalis trophozoites. Saquinavir was not effective. These findings are significant considering the association between human immunodeficiency virus and T. vaginalis, and between G. duodenalis and homosexual behaviour.

Synthesis and Evaluation of Antimalarial Properties of Novel 4‐Aminoquinoline Hybrid Compounds

Publisher: Wiley

Date: 03-06-2014

DOI: 10.1111/CBDD.12335

Abstract: Pharmacophore hybridization has recently been employed in the search for antimalarial lead compounds. This approach chemically links two pharmacophores, each with their own antimalarial activity and ideally with different modes of action, into a single hybrid molecule with the goal to improve therapeutic properties. In this paper, we report the synthesis of novel 7-chloro-4-aminoquinoline rimary sulfonamide hybrid compounds. The chlorinated 4-aminoquinoline scaffold is the core structure of chloroquine, an established antimalarial drug, while the primary sulfonamide functional group has a proven track record of efficacy and safety in many clinically used drugs and was recently shown to exhibit some antimalarial activity. The activity of the hybrid compounds was determined against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. While the hybrid compounds had lower antimalarial activity when compared to chloroquine, they demonstrated a number of interesting structure-activity relationship (SAR) trends including the potential to overcome the resistance profile of chloroquine.

Design and Synthesis of Novel Anti‐Plasmodial Histone Deacetylase Inhibitors Containing an Alkoxyamide Connecting Unit

Publisher: Wiley

Date: 20-03-2017

DOI: 10.1002/ARDP.201600347

Abstract: Despite recent declines in mortality, malaria remains an important global health problem. New therapies are needed, including new drugs with novel modes of action compared to existing agents. Among new potential therapeutic targets for malaria, inhibition of parasitic histone deacetylases (HDACs) is a promising approach. Homology modeling of PfHDAC1, a known target of some anti-plasmodial HDAC inhibitors, revealed a unique threonine residue at the rim of the active site in close proximity to the location of the cap group of vorinostat-type HDAC inhibitors. Aiming to obtain HDAC inhibitors with potent and preferential anti-plasmodial activity, we synthesized a mini-library of alkoxyamide-based HDAC inhibitors containing hydrogen bond acceptors in the cap group. Using a 5-step synthetic route, 12 new inhibitors were synthesized and assayed against Plasmodium falciparum asexual blood stage parasites (clones 3D7 and Dd2) and human cells (HepG2). The most active compound 6h (Pf3D7 IC

Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus.

Publisher: Springer Science and Business Media LLC

Date: 31-05-2017

DOI: 10.1186/S13071-017-2191-8

One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites

Publisher: Elsevier BV

Date: 10-2018

DOI: 10.1016/J.EJMECH.2018.09.018

Chemical investigation of an antimalarial Chinese medicinal herb Picrorhiza scrophulariiflora

Publisher: Elsevier BV

Date: 11-2013

DOI: 10.1016/J.BMCL.2013.08.077

Abstract: An antimalarial medicinal plant Picrorhiza scrophulariiflora was chemically investigated as part of our ongoing research in traditional chinese medicines (TCM). Mass directed fractionation of the active part of the crude extract led to the isolation of ten main components, three new compounds (1-3) and seven known compounds (4-10). Compound 10 inhibited the growth of the Plasmodium falciparum 3D7 malarial parasite line, with an IC50 value of 8.3μM. This compound accounted for ∼95% of P. falciparum growth inhibitory activity in the crude extract confirming, for this TCM, that a single compound was responsible for the antimalarial activity.

Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents

Publisher: Elsevier BV

Date: 05-2000

DOI: 10.1016/S0020-7519(00)00043-6

Abstract: The histones of Plasmodium falciparum represent a potential new target for anti-malarial compounds. A naturally occurring compound, apicidin, has recently been shown to inhibit the in vitro growth of P. falciparum. Apicidin was shown to hyperacetylate histones, suggesting that its mode of action is through histone deacetylase inhibition. We have tested the ability of known histone deacetylase inhibitors, mammalian tumour suppressor compounds, and cytodifferentiating agents to inhibit the in vitro growth of a drug sensitive and resistant strain of P. falciparum. Seven of the tested compounds had microM IC50 values, and trichostatin A, a histone deacetylation inhibitor and cytodifferentiating agent, was active at low nM concentrations. One compound, suberic acid bisdimethylamide, which selectively arrests tumour cells as opposed to normal mammalian cells, had an in vivo cytostatic effect against the acute murine malaria Plasmodium berghei, and one round of treatment with the compound failed to select for resistant mutations. These results suggest a promising role for histone deacetylase inhibitors and cytodifferentiating agents as antimalarial drug candidates.

Antimalarial Isocyano and Isothiocyanato Sesquiterpenes with Tri- and Bicyclic Skeletons from the Nudibranch Phyllidia ocellata

Publisher: American Chemical Society (ACS)

Date: 09-06-2015

DOI: 10.1021/ACS.JNATPROD.5B00354

Abstract: Five new isocyano/isothiocyanato sesquiterpenes (1-5) with tri- or bicyclic carbon skeletons have been characterized from Australian specimens of the nudibranch Phyllidia ocellata. Spectroscopic analyses at 900 MHz were informed by DFT calculations. The 1S, 5S, 8R configuration of 2-isocyanoclovene (1) was determined by X-ray crystallographic analysis of formamide 6. A biosynthetic pathway to clovanes 1 and 2 from epicaryolane precursors is proposed. Isocyanides 1, 2, and 4 showed activity against Plasmodium falciparum (IC50 0.26-0.30 μM), while isothiocyanate 3 and formamide 6 had IC50 values of >10 μM.

Reply to Savarino et al.

Publisher: Oxford University Press (OUP)

Date: 15-04-2005

DOI: 10.1086/428782

Pestalactams A-C: Novel caprolactams from the endophytic fungus Pestalotiopsis sp.

Publisher: Royal Society of Chemistry (RSC)

Date: 2010

DOI: 10.1039/B924169H

Abstract: Chemical investigations of a fermentation culture from the endophytic fungus Pestalotiopsis sp. yielded three novel caprolactams, pestalactams A-C (). The structures of were determined by analysis of 1D and 2D-NMR, UV, IR, and MS data. The structure of pestalactam A was confirmed following single crystal X-ray diffraction analysis. Pestalactams A-C are the first C-7 alkylated caprolactam natural products to be reported. Pestalactams A () and B () were tested against two different strains of the malaria parasite Plasmodium falciparum (3D7 and Dd2), and the mammalian cell lines, MCF-7 and NFF, and showed modest in vitro activity in all assays.

Inhibition of Chondroitin-4-Sulfate-Specific Adhesion of Plasmodium falciparum -Infected Erythrocytes by Sulfated Polysaccharides

Publisher: American Society for Microbiology

Date: 07-2005

DOI: 10.1128/IAI.73.7.4288-4294.2005

Abstract: Adhesion of Plasmodium falciparum -infected erythrocytes to placental chondroitin 4-sulfate (CSA) has been linked to the severe disease outcome of pregnancy-associated malaria. Soluble polysaccharides that release mature-stage parasitized erythrocytes into the peripheral circulation may help elucidate these interactions and have the potential to aid in developing therapeutic strategies. We have screened a panel of 11 sulfated polysaccharides for their capacities to inhibit adhesion of infected erythrocytes to CSA expressed on CHO-K1 cells and ex vivo human placental tissue. Two carrageenans and a cellulose sulfate (CS10) were able to inhibit adhesion to CSA and to cause already bound infected erythrocytes to de-adhere in a dose-dependent manner. CS10, like CSA and in contrast to all other compounds tested, remained bound to infected erythrocytes after washing and continued to inhibit binding. Both carrageenans and CS10 inhibited adhesion to placental tissue. Although highly sulfated dextran sulfate can inhibit CSA-mediated adhesion to CHO cells, this polysaccharide lified adhesion to placental tissue severalfold, demonstrating the importance of evaluating inhibitory compounds in systems as close to in vivo as possible. Interestingly, and in contrast to all other compounds tested, which had a random distribution of sulfate groups, CS10 exhibited a clustered sulfate pattern along the polymer chain, similar to that of the undersulfated placental CSA preferred by placental-tissue-binding infected erythrocytes. Therefore, the specific antiadhesive capacity observed here seems to depend not only on the degree of charge and sulfation but also on a particular pattern of sulfation.

Antimalarial natural products from traditional chinese medicinal herbs

Publisher: Georg Thieme Verlag KG

Date: 07-2012

DOI: 10.1055/S-0032-1320899

Thymidine kinase-independent click chemistry DNADetect™ probes for DNA proliferation assessment in malaria parasites

Publisher: Cold Spring Harbor Laboratory

Date: 27-03-2023

DOI: 10.1101/2023.03.26.534296

Abstract: Metabolic chemical probes are small molecule reagents that utilise naturally occurring biosynthetic enzymes for in situ incorporation into biomolecules of interest. These reagents can be used to label, detect, and track important biological processes within living cells including protein synthesis, protein glycosylation and nucleic acid proliferation. A limitation of current chemical probes, which have largely focused on mammalian cells, is that they often cannot be applied to other organisms due to metabolic differences. For ex le, the thymidine derivative 5-ethynyl-2’-deoxyuridine (EdU) is a gold standard metabolic chemical probe for assessing DNA proliferation in mammalian cells however is unsuitable for the study of malaria parasites due to Plasmodium species lacking the thymidine kinase enzyme that is essential for metabolism of EdU. Herein we report the design and synthesis of new thymidine-based probes that sidestep the requirement for a thymidine kinase enzyme in Plasmodium . Two of these DNADetect™ probes exhibit robust labelling of replicating asexual intraerythrocytic P. falciparum parasites, as determined by flow cytometry using copper catalysed azide-alkyne cycloaddition (CuAAC) to a fluorescent azide. The DNADetect™ chemical probes are synthetically accessible and thus can be made widely available to researchers as tools to further understand the biology of different Plasmodium species, including laboratory lines and clinical isolates.

Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

Publisher: Public Library of Science (PLoS)

Date: 28-07-2016

DOI: 10.1371/JOURNAL.PPAT.1005763

Pharmacodynamics of once- versus twice-daily dosing of nebulized amikacin in an in vitro Hollow-Fiber Infection Model against 3 clinical isolates of Pseudomonas aeruginosa

Publisher: Elsevier BV

Date: 06-2021

DOI: 10.1016/J.DIAGMICROBIO.2021.115329

Recovery of adhesion to chondroitin‐4‐sulphate in Plasmodium falciparum var ^CSA disruption mutants by antigenically similar PfEMP1 variants

Publisher: Wiley

Date: 08-2003

DOI: 10.1046/J.1365-2958.2003.03595.X

Abstract: Protection against maternal malaria has been associated with the acquisition of a specific antibody response that prevents adhesion of Plasmodium falciparum-infected erythrocytes to the glycosaminoglycan chondroitin-4-sulphate (CSA), which is present in the placental intervillous space. These antibodies are directed against variant forms of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) that mediate binding to CSA. We have generated insertional disruption mutants of the gene encoding the CSA-binding phenotype in the P. falciparum clone FCR3 (varCSA) to test the hypothesis that strategies targeting the parasite's determinant for this adhesive phenotype may prevent sequestration of infected erythrocytes in the placenta and hence the development of maternal malaria. The varCSA-disruption mutants were initially unable to adhere to CSA however, they could recover the phenotype after repeated selection over CSA. We show that recovery of CSA binding is varCSA independent and mediated by the activation of a novel var variant. Importantly, the corresponding PfEMP1 protein reacts with a monoclonal antibody recognizing the DBL3 gamma domain of the varCSA gene product, indicating that the DBL3 gamma CSA-binding domains are conserved between these PfEMP1-binding variants. Our data support strategies exploring these conserved epitopes as vaccine candidates against maternal malaria.

Antimalarial activity of sera from subjects taking HIV protease inhibitors

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 30-03-2007

DOI: 10.1097/QAD.0B013E328031F41A

Defining the targets of antiparasitic compounds.

Publisher: Elsevier BV

Date: 05-2016

DOI: 10.1016/J.DRUDIS.2016.01.002

Abstract: The treatment of major human parasitic infections is dependent on drugs that are plagued by issues of drug resistance. New chemotherapeutics with novel mechanisms of action (MOA) are desperately needed to combat multi-drug-resistant parasites. Although widespread screening strategies are identifying potential new hits for development against most major human parasitic diseases, in many cases such efforts are hindered by limited MOA data. Although MOA data are not essential for drug development, they can facilitate compound triage and provide a mechanism to combat drug resistance. Here we describe and discuss methods currently used to identify the targets of antiparasitic compounds, which could circumvent this bottleneck and facilitate the development of new antiparasitic drugs.

HIV and malaria co-infection: interactions and consequences of chemotherapy

Publisher: Elsevier BV

Date: 06-2008

DOI: 10.1016/J.PT.2008.03.008

Abstract: The global epidemiology of HIV/AIDS and malaria overlap because a significant number of HIV-infected in iduals live in regions with different levels of malaria transmission. Although the consequences of co-infection with HIV and malaria parasites are not fully understood, available evidence suggests that the infections act synergistically and together result in worse outcomes. The importance of understanding chemotherapeutic interactions during malaria and HIV co-infection is now being recognized. We know that some antimalarial drugs have weak antiretroviral effects however, recent studies have also demonstrated that certain antiretroviral agents can inhibit malaria-parasite growth. Here, we discuss recent findings on the impact of HIV/AIDS and malaria co-infection and the possible roles of chemotherapy in improving the treatment of these diseases.

Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold

Publisher: Royal Society of Chemistry (RSC)

Date: 2015

DOI: 10.1039/C4OB01849D

Abstract: A series of amide and urea analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity.

Evidence for trafficking of PfEMP1 to the surface of P. falciparum-infected erythrocytes via a complex membrane network

Publisher: Elsevier BV

Date: 06-2003

DOI: 10.1078/0171-9335-00319

Abstract: The human malarial parasite Plasmodium falciparum exports virulence determinants, such as the P. falciparum erythrocyte membrane protein 1 (PfEMP1), beyond its own periplasmatic boundaries to the surface of its host erythrocyte. This is remarkable given that erythrocytes lack a secretory pathway. Here we present evidence for a continuous membrane network of parasite origin in the erythrocyte cytoplasm. Co-localizations with antibodies against PfEMP1, PfExp-1, Pf332 and PfSbpl at the light and electron microscopical level indicate that this membrane network is composed of structures that have been previously described as tubovesicular membrane network (TVM), Maurer's clefts and membrane whorls. This membrane network could also be visualized in vivo by vital staining of infected erythrocytes with the fluorescent dye LysoSensor Green DND-153. At sites where the membrane network abuts the erythrocyte plasma membrane we observed small vesicles of 15-25 nm in size, which seem to bud from and/or fuse with the membrane network and the erythrocyte plasma membrane, respectively. On the basis of our data we hypothesize that this membrane network of parasite origin represents a novel secretory organelle that is involved in the trafficking of PfEMP1 across the erythrocyte cytoplasm.

Antimalarial Activity of Pyrroloiminoquinones from the Australian Marine Sponge Zyzzya sp

Publisher: American Chemical Society (ACS)

Date: 20-06-2012

DOI: 10.1021/JM3002795

Abstract: A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC(50) values of 13 and 18 nM against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine C (1) displayed selectivity indices of >200 against HEK293 cells and inhibited both ring and trophozoite stages of the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) and damirones A (6) and B (7) were also isolated from the same marine sponge (Zyzzya sp.). Compounds 2-4 displayed potent growth inhibitory activity (IC(50) < 100 nM) against both P. falciparum lines and only moderate cytotoxicity against HEK293 cells (IC(50) = 1-4 μM). Makaluvamine G (3) was not toxic to mice and suppressed parasite growth in P. berghei infected mice following subcutaneous administration at 8 mg kg(-1) day(-1).

Carrageenans inhibit the in vitro growth of Plasmodium falciparum and cytoadhesion to CD36

Publisher: Springer Science and Business Media LLC

Date: 13-07-2005

DOI: 10.1007/S00436-005-1426-3

Abstract: Carbohydrates are implicated in many of the invasive and adhesive interactions that occur between Plasmodium falciparum malaria parasites and human host cells, including invasion of sporozoites into hepatocytes, entry of merozoites into new host erythrocytes during asexual blood-stage replication, adhesion of infected erythrocytes to uninfected erythrocytes (rosetting) and to a number of host endothelial receptors including ICAM-1, CD36 and chondroitin-4-sulphate. In addition to increasing our understanding of host-parasite interactions, the investigation of carbohydrates with differing levels and patterns of sulphation as inhibitors may contribute to the development of novel therapeutics targeting malaria. Here we show that three polysaccharides derived from seaweed (carrageenans) with differing sulphation levels and patterns can inhibit the in vitro erythrocytic invasion and growth of both drug sensitive and drug resistant P. falciparum lines and the adhesion of parasitized erythrocytes to the human glycoprotein CD36.

Total synthesis of thiaplakortone a: derivatives as metabolically stable leads for the treatment of malaria.

Publisher: American Chemical Society (ACS)

Date: 02-01-2013

DOI: 10.1021/ML400447V

Antimalarial Activity of Natural Product Extracts from Papua New Guinean and Australian Plants against Plasmodium falciparum

Publisher: Wiley

Date: 10-2008

DOI: 10.1002/PTR.2510

Abstract: In the search for new antimalarial compounds, a subset of a natural product extract library prepared from plant s les collected from Papua New Guinea and Australia was screened for in vitro activity against the chloroquine-sensitive 3D7 and chloroquine-resistant Dd2 strains of Plasmodium falciparum. Using the incorporation of ((3)H)-hypoxanthine into parasite nucleic acid as a marker of growth, 93 of the 794 extracts screened displayed >40% inhibition against 3D7 infected erythrocytes at 312 microge/mL. Antimalarial activity was confirmed in 48 of these extracts against both 3D7 and Dd2 infected erythrocytes at concentrations between 78 and 390 microge/mL, 14 of which caused >90% growth inhibition of 3D7 at the lowest concentration screened. Extracts were also tested for mammalian cell cytotoxicity to evaluate selectivity of action.

An ELISA method to assess HDAC inhibitor-induced alterations to P. falciparum histone lysine acetylation

Publisher: Elsevier BV

Date: 12-2020

DOI: 10.1016/J.IJPDDR.2020.10.010

Synergistic interactions of the antiretroviral protease inhibitors saquinavir and ritonavir with chloroquine and mefloquine against Plasmodium falciparum in vitro

Publisher: American Society for Microbiology

Date: 02-2007

DOI: 10.1128/AAC.00840-06

Abstract: The antimalarial activity of several antiretroviral protease inhibitor combinations was investigated. Data demonstrate that ritonavir and saquinavir behave synergistically with chloroquine and mefloquine. These data, and interactions with pepstatin-A, E-64, and bestatin, suggest that human immunodeficiency virus protease inhibitors do not target digestive-vacuole plasmepsins.

Psammaplysin H, a new antimalarial bromotyrosine alkaloid from a marine sponge of the genus Pseudoceratina

Publisher: Elsevier BV

Date: 2011

DOI: 10.1016/J.BMCL.2010.11.081

Abstract: Mass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from a marine sponge of the genus Pseudoceratina resulted in the purification of a new antimalarial bromotyrosine alkaloid, psammaplysin H (1), along with the previously isolated analogs psammaplysins G (2) and F (3). The structure of 1 was elucidated following 1D and 2D NMR, and MS data analysis. All compounds were tested in vitro against the 3D7 line of Plasmodium falciparum and mammalian cell lines (HEK293 and HepG2), with 1 having the most potent (IC(50) 0.41μM) and selective (>97-fold) antimalarial activity.

Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria

Publisher: American Society for Microbiology

Date: 02-2006

DOI: 10.1128/AAC.50.2.639-648.2006

Abstract: Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone

Publisher: Springer Science and Business Media LLC

Date: 03-05-2019

DOI: 10.1038/S42003-019-0397-3

Abstract: Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil’s action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function. Here we demonstrate that proguanil, and cyclization-blocked analogue tBuPG, have potent, but slow-acting, in vitro anti-plasmodial activity. Activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast dihydroorotate dehydrogenase-expressing parasites, proguanil and tBuPG slow-action remains, while bc1-inhibitor activity switches from comparatively fast to slow-acting. Like proguanil, tBuPG has activity against P. berghei liver-stage parasites. Both analogues act synergistically with bc1-inhibitors against blood-stages in vitro, however cycloguanil antagonizes activity. Together, these data suggest that proguanil is a potent slow-acting anti-plasmodial agent, that bc1 is essential to parasite survival independent of dihydroorotate dehydrogenase-activity, that Malarone® is a triple-drug combination that includes antagonistic partners and that a cyclization-blocked proguanil may be a superior combination partner for bc1-inhibitors in vivo.

Antiplasmodial activity of the natural product compounds alstonine and himbeline

Publisher: Elsevier BV

Date: 08-2021

DOI: 10.1016/J.IJPDDR.2021.04.003

Proteomic analysis of Plasmodium falciparum histone deacetylase 1 complex proteins

Publisher: Elsevier BV

Date: 03-2019

DOI: 10.1016/J.EXPPARA.2019.01.008

Abstract: Plasmodium falciparum histone deacetylases (PfHDACs) are an important class of epigenetic regulators that alter protein lysine acetylation, contributing to regulation of gene expression and normal parasite growth and development. PfHDACs are therefore under investigation as drug targets for malaria. Despite this, our understanding of the biological roles of these enzymes is only just beginning to emerge. In higher eukaryotes, HDACs function as part of multi-protein complexes and act on both histone and non-histone substrates. Here, we present a proteomics analysis of PfHDAC1 immunoprecipitates, identifying 26 putative P. falciparum complex proteins in trophozoite-stage asexual intraerythrocytic parasites. The co-migration of two of these (P. falciparum heat shock proteins 70-1 and 90) with PfHDAC1 was validated using Blue Native PAGE combined with Western blot. These data provide a snapshot of possible PfHDAC1 interactions and a starting point for future studies focused on elucidating the broader function of PfHDACs in Plasmodium parasites.

Structure-Activity and Structure-Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity.

Publisher: Wiley

Date: 19-02-2019

DOI: 10.1002/CMDC.201800808

Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment.

Publisher: Elsevier BV

Date: 11-2013

DOI: 10.1016/J.BMCL.2013.09.015

Abstract: Despite the urgent need for effective antimalarial drugs with novel modes of action no new chemical class of antimalarial drug has been approved for use since 1996. To address this, we have used a rational approach to investigate compounds comprising the primary benzene sulfonamide fragment as a potential new antimalarial chemotype. We report the in vitro activity against Plasmodium falciparum drug sensitive (3D7) and resistant (Dd2) parasites for a panel of fourteen primary benzene sulfonamide compounds. Our findings provide a platform to support the further evaluation of primary benzene sulfonamides as a new antimalarial chemotype, including the identification of the target of these compounds in the parasite.

Identification of novel quinazoline derivatives as potent antiplasmodial agents.

Publisher: Elsevier BV

Date: 2018

DOI: 10.1016/J.EJMECH.2018.10.041

Abstract: Despite the recent reductions in the global burden of malaria, this disease remains a devastating cause of death in tropical and subtropical regions. As there is no broadly effective vaccine for malaria, prevention and treatment still rely on chemotherapy. Unfortunately, emerging resistance to the gold standard artemisinin combination therapies means that new drugs with novel modes of action are urgently needed. In this context, Plasmodium histone modifying enzymes have emerged as potential drug targets, prompting us to develop and optimize compounds directed against such epigenetic targets. A panel of 51 compounds designed to target different epigenetic enzymes were screened for activity against Plasmodium falciparum parasites. Based on in vitro activity against drug susceptible and drug-resistant P. falciparum lines, selectivity index criterion and favorable pharmacokinetic properties, four compounds, one HDAC inhibitor (1) and three DNMT inhibitors (37, 43 and 45), were selected for preclinical studies in a mouse model of malaria. In vivo data showed that 37, 43 and 45 exhibited oral efficacy in the mouse model of Plasmodium berghei infection. These compounds represent promising starting points for the development of novel antimalarial drugs.

Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages

Publisher: Elsevier BV

Date: 07-2014

DOI: 10.1016/J.EJMECH.2014.05.050

Effect of sequence variation in Plasmodium falciparum histidine- rich protein 2 on binding of specific monoclonal antibodies: Implications for rapid diagnostic tests for malaria

Publisher: American Society for Microbiology

Date: 08-2006

DOI: 10.1128/JCM.02557-05

Abstract: The ability to accurately diagnose malaria infections, particularly in settings where laboratory facilities are not well developed, is of key importance in the control of this disease. Rapid diagnostic tests (RDTs) offer great potential to address this need. Reports of significant variation in the field performance of RDTs based on the detection of Plasmodium falciparum histidine-rich protein 2 (HRP2) (PfHRP2) and of significant sequence polymorphism in PfHRP2 led us to evaluate the binding of four HRP2-specific monoclonal antibodies (MABs) to parasite proteins from geographically distinct P. falciparum isolates, define the epitopes recognized by these MABs, and relate the copy number of the epitopes to MAB reactivity. We observed a significant difference in the reactivity of the same MAB to different isolates and between different MABs tested with single isolates. When the target epitopes of three of the MABs were determined and mapped onto the peptide sequences of the field isolates, significant variability in the frequency of these epitopes was observed. These findings support the role of sequence variation as an explanation for variations in the performance of HRP2-based RDTs and point toward possible approaches to improve their diagnostic sensitivities.

Comparison of different PCR protocols for the detection and diagnosis of Plasmodium falciparum

Publisher: Springer Science and Business Media LLC

Date: 07-09-2005

DOI: 10.1007/S00436-005-1479-3

Abstract: An assessment of differing PCR protocols for the diagnosis of Plasmodium falciparum infection was performed on s les from an area of holoendemic malaria transmission in western Burkina Faso. The PCR protocols had generally high sensitivities (>92%) and specificities (>69%), but the negative predictive values (NPV) were moderate and differed widely among the PCR protocols tested. These PCR protocols that lified either the P. falciparum pfcrt gene or the small subunit ribosomal DNA were the most reliable diagnostic tools. However, the moderate NPV imply that more than one PCR protocol should be used for diagnosis in holoendemic areas.

Synthesis and antimalarial evaluation of novel benzopyrano[4,3-b]benzopyran derivatives

Publisher: Elsevier BV

Date: 09-2011

DOI: 10.1016/J.BMC.2011.07.009

Abstract: 7-Methoxyflavenes and 5,7,8-trimethoxyflavenes were found to undergo stereoselective acid-catalyzed rearrangement to generate the benzopyrano[4,3-b]benzopyran ring system present in the natural product, dependensin. Dependensin and its analogs were subjected to antimalarial growth inhibition assays against Plasmodium falciparum and found to have IC(50) values ranging between 1.9 and 3.9 μM.

RAP1 controls rhoptry targeting of RAP2 in the malaria parasite Plasmodium falciparum

Publisher: Wiley

Date: 06-2000

DOI: 10.1093/EMBOJ/19.11.2435

FgoI, a type II restriction endonuclease from the thermoanaerobe Fervidobacterium gondwanense AB39(T)

Publisher: Elsevier BV

Date: 10-1998

DOI: 10.1006/ANAE.1998.0167

Abstract: Restriction endonuclease activity was detected in 11 out of 13 Fervidobacterium isolates, including F. islandicum H21(T), F. gondwanense AB39(T), and nine other Fervidobacterium-like strains isolated from the Great Artesian Basin of Australia. The restriction endonuclease from F. gondwanense AB39(T) was partially purified and designated FgoI. FgoI recognized a 4 nucleotide sequence 5'-CTAG-3' and cleaved between nucleotides C and T to produce a 2 base 5' overhang (5'-C/TAG-3'). As predicted from the enzyme recognition and cleavage specificity, FgoI was found to cleave delta DNA 13 times, phiX174 three times, pBR322 five times, pUC18 four times, and pSK six times. FgoI exhibited a broad temperature optimum range (between 60 to 70 degrees C) and was active at pH 6.5 to 8.5, but not at pH 9.0. Manganese could replace magnesium as a cofactor for activity, but not cobalt chloride, calcium chloride, cupric chloride, or zinc chloride. The restriction endonuclease was completely inactivated by phenol/chloroform extraction and was heat inactivated at 80 degrees C for 60 min or at 100 degrees C for 15 min. FgoI has been identified as a heat stable isoschizomer of the Type II restriction endonucleases, MaeI and BfaI.

Drug repurposing and human parasitic protozoan diseases.

Publisher: Elsevier BV

Date: 08-2014

DOI: 10.1016/J.IJPDDR.2014.02.002

A novel in vitro image-based assay identifies new drug leads for giardiasis

Publisher: Elsevier BV

Date: 04-2017

DOI: 10.1016/J.IJPDDR.2017.01.005

Antimalarial activity of azadipeptide nitriles

Publisher: Elsevier BV

Date: 2010

DOI: 10.1016/J.BMCL.2009.10.122

Apparent bias for P. falciparum parasites carrying the wild-type pfcrt allele in the placenta

Publisher: Springer Science and Business Media LLC

Date: 11-02-2010

DOI: 10.1007/S00436-010-1756-7

Abstract: Resistance to chloroquine has been linked to polymorphisms within the pfcrt gene of the human malarial parasite Plasmodium falciparum. Here, we have investigated the prevalence of the pfcrt allele associated with chloroquine resistance in the peripheral blood and the placenta of pregnant women diagnosed with a P. falciparum infection. Our molecular epidemiological data show an unequal distribution with a significant under-representation of parasites carrying the mutated pfcrt allele in the placenta, as compared to the peripheral blood. In comparison, no differences were seen with regard to pfmdr1 polymorphisms of these parasites. Our data suggest a selective disadvantage of the polymorphic and a selective advantage of the wild-type pfcrt haplotype in the placenta, supporting the model that the human host provides various microenvironments that favor genetically distinct P. falciparum populations.

Ex VivoActivity of Histone Deacetylase Inhibitors against Multidrug-Resistant Clinical Isolates ofPlasmodium falciparumandP. vivax

Publisher: American Society for Microbiology

Date: 03-2011

DOI: 10.1128/AAC.01220-10

Abstract: Histone acetylation plays an important role in regulating gene transcription and silencing in Plasmodium falciparum . Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent in vitro activity against drug-resistant and -sensitive laboratory strains of P. falciparum , raising their potential as a new class of antimalarial compounds. In the current study, stage-specific ex vivo susceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates of P. falciparum ( n = 24) and P. vivax ( n = 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of both P. falciparum (median 50% inhibitory concentrations [IC 50 s] of 310, 533, and 266 nM) and P. vivax (median IC 50 s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for P. falciparum and mefloquine for P. vivax indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivo against P . vivax schizont maturation, comparable to that in P. falciparum , suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivo efficacy of HDAC inhibitors in Plasmodium spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.

Stronger activity of human immunodeficiency virus type 1 protease inhibitors against clinical isolates of Plasmodium vivax than against those of P. falciparum

Publisher: American Society for Microbiology

Date: 07-2008

DOI: 10.1128/AAC.00169-08

Abstract: Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors (PIs) inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during human immunodeficiency virus type 1 (HIV-1) and malaria coinfection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic PIs, saquinavir (SQV) and ritonavir (RTV), against P. vivax ( n = 30) and P. falciparum ( n = 20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thailand-Myanmar border. The median 50% inhibitory concentration values of P. vivax to RTV and SQV were 2,233 nM (range, 732 to 7,738 nM) and 4,230 nM (range, 1,326 to 8,452 nM), respectively, both within the therapeutic concentration range commonly found for patients treated with these PIs. RTV was fourfold more effective at inhibiting P. vivax than it was at inhibiting P. falciparum , compared to a twofold difference in SQV sensitivity. An increased P. falciparum mdr1 copy number was present in 33% (3/9) of isolates and that of P. vivax mdr1 was present in 9% of isolates (2/22), but neither was associated with PI sensitivity. The inter- Plasmodium sp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum . PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients who reside in areas where multidrug-resistant P. vivax or P. falciparum is found.

Impact of the Epithelial Lining Fluid Milieu on Amikacin Pharmacodynamics Against Pseudomonas aeruginosa

Publisher: Springer Science and Business Media LLC

Date: 02-04-2021

DOI: 10.1007/S40268-021-00344-5

Direct Activation of Human Endothelial Cells by Plasmodium falciparum -Infected Erythrocytes

Publisher: American Society for Microbiology

Date: 06-2005

DOI: 10.1128/IAI.73.6.3271-3277.2005

Abstract: Cytoadherence of Plasmodium falciparum -infected erythrocytes (PRBC) to endothelial cells causes severe clinical disease, presumably as a of result perfusion failure and tissue hypoxia. Cytoadherence to endothelial cells is increased by endothelial cell activation, which is believed to occur in a paracrine fashion by mediators such as tumor necrosis factor alpha (TNF-α) released from macrophages that initially recognize PRBC. Here we provide evidence that PRBC directly stimulate human endothelial cells in the absence of macrophages, leading to increased expression of adhesion-promoting molecules, such as intercellular adhesion molecule 1. Endothelial cell stimulation by PRBC required direct physical contact for a short time (30 to 60 min) and was correlated with parasitemia. Gene expression profiling of endothelial cells stimulated by PRBC revealed increased expression levels of chemokine and adhesion molecule genes. PRBC-stimulated endothelial cells especially showed increased expression of molecules involved in parasite adhesion but failed to express molecules promoting leukocyte adhesion, such as E-selectin and vascular cell adhesion molecule 1, even after challenge with TNF-α. Collectively, our data suggest that stimulation of endothelial cells by PRBC may have two effects: prevention of parasite clearance through increased cytoadherence and attenuation of leukocyte binding to endothelial cells, thereby preventing deleterious immune reactivity.

Discovery of a new family of carbonic anhydrases in the malaria pathogen Plasmodium falciparum —The η-carbonic anhydrases

Publisher: Elsevier BV

Date: 09-2014

DOI: 10.1016/J.BMCL.2014.08.015

Abstract: The genome of the protozoan parasite Plasmodium falciparum, the causative agent of the most lethal type of human malaria, contains a single gene annotated as encoding a carbonic anhydrase (CAs, EC 4.2.1.1) thought to belong to the α-class, PfCA. Here we demonstrate the kinetic properties of PfCA for the CO2 hydration reaction, as well as an inhibition study of this enzyme with inorganic and complex anions and other molecules known to interact with zinc proteins, including sulfamide, sulfamic acid, and phenylboronic/arsonic acids, detecting several low micromolar inhibitors. A closer examination of the sequence of this and the CAs from other Plasmodium spp., as well as a phylogenetic analysis, revealed that these protozoa encode for a yet undisclosed, new genetic family of CAs termed the η-CA class. The main features of the η-CAs are described in this report.

Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

Publisher: American Society for Microbiology

Date: 20-08-2020

DOI: 10.1128/AAC.00879-20

Abstract: Given that aminoglycosides, such as amikacin, may be used for multidrug-resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P. aeruginosa to inform ventilator-associated pneumonia (VAP) and sepsis treatment choices. A hollow-fiber infection model with two P. aeruginosa isolates (MICs of 2 and 8 mg/liter) with an initial inoculum of ∼10 8 CFU/ml was used to test different amikacin dosing regimens.

Antimalarial asexual stage-specific and gametocytocidal activities of HIV protease inhibitors

Publisher: American Society for Microbiology

Date: 03-2010

DOI: 10.1128/AAC.01512-09

Abstract: The stage-specific antimalarial activities of a panel of antiretroviral protease inhibitors (PIs), including two nonpeptidic PIs (tipranavir and darunavir), were tested in vitro against Plasmodium falciparum . While darunavir demonstrated limited antimalarial activity (effective concentration [EC 50 ], μM), tipranavir was active at clinically relevant concentrations (EC 50 , 12 to 21 μM). Saquinavir, lopinavir, and tipranavir preferentially inhibited the growth of mature asexual-stage parasites (24 h postinvasion). While all of the PIs tested inhibited gametocytogenesis, tipranavir was the only one to exhibit gametocytocidal activity.

HDAC inhibitors in parasitic diseases

Publisher: Wiley

Date: 29-11-2012

DOI: 10.1038/ICB.2011.97

Abstract: Parasitic diseases cause significant global morbidity and mortality, particularly in underdeveloped regions of the world. Malaria alone causes ~800000 deaths each year, with children and pregnant women being at highest risk. There is no licensed vaccine available for any human parasitic disease and drug resistance is compromising the efficacy of many available anti-parasitic drugs. This is driving drug discovery research on new agents with novel modes of action. Histone deacetylase (HDAC) inhibitors are being investigated as drugs for a range of diseases, including cancers and infectious diseases such as HIV/AIDS, and several parasitic diseases. This review focuses on the current state of knowledge of HDAC inhibitors targeted to the major human parasitic diseases malaria, schistosomiasis, trypanosomiasis, toxoplasmosis and leishmaniasis. Insights are provided into the unique challenges that will need to be considered if HDAC inhibitors are to be progressed towards clinical development as potential new anti-parasitic drugs.

Synthesis, antimalarial properties, and SAR studies of alkoxyurea-based HDAC inhibitors.

Publisher: Wiley

Date: 04-02-2014

DOI: 10.1002/CMDC.201300469

Abstract: Histone deacetylase (HDAC) inhibitors are an emerging class of potential antimalarial drugs. We investigated the antiplasmodial properties of 16 alkoxyurea-based HDAC inhibitors containing various cap and zinc binding groups (ZBGs). Ten compounds displayed sub-micromolar activity against the 3D7 line of Plasmodium falciparum. Structure-activity relationship studies revealed that a hydroxamic acid ZBG is crucial for antiplasmodial activity, and that the introduction of bulky alkyl substituents to cap groups increases potency against asexual blood-stage parasites. We also demonstrate that selected compounds cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs. To assess the selectivity of alkoxyurea-based HDAC inhibitors for parasite over normal mammalian cells, the cytotoxicity of representative compounds was evaluated against neonatal foreskin fibroblast (NFF) cells. The most active compound, 6-((3-(4-(tert-butyl)phenyl)ureido)oxy)-N-hydroxyhexanamide (1 e, Pf3D7 IC50 : 0.16 μM) was 31-fold more toxic against the asexual blood stages than towards normal mammalian cells. Moreover, a subset of four structurally erse HDAC inhibitors revealed moderate activity against late-stage (IV-V) gametocytes.

Efficacy of vaccines containing rhoptry-associated proteins RAP1 and RAP2 of Plasmodium falciparum in Saimiri boliviensis monkeys

Publisher: American Society of Tropical Medicine and Hygiene

Date: 04-2000

DOI: 10.4269/AJTMH.2000.62.466

Abstract: A vaccine trial was conducted with rhoptry-associated proteins 1 and 2 (RAP1 and RAP2) of Plasmodium falciparum in Saimiri boliviensis monkeys to compare the ability of parasite-derived (PfRAP1 and 2) and recombinant proteins (rRAP1 and 2) to induce protective immune responses and to find adjuvants suitable for use in humans. Eight groups of 6 monkeys each were immunized with parasite-derived or recombinant RAP1 and 2 with Freund's complete adjuvant (FCA) followed by Freund's incomplete adjuvant (FIA), Montanide ISA720 adjuvant, or CRL1005 adjuvant. Recombinant RAP1 and RAP2 were also administered separately, with Montanide ISA720. After 3 immunizations, monkeys were challenged by iv inoculation of 50,000 parasites of the Uganda Palo Alto strain of P. falciparum. Of the animals vaccinated using FCA/FIA, 1 of 6 control monkeys, 3 of 6 immunized with PfRAP1 and 2, and 2 of 6 with rRAP1 and 2 did not require drug treatment. Of the monkeys vaccinated with Montanide ISA720 adjuvant, 0 of the 6 control monkeys, 2 of 6 immunized with RAP1 and 2, 1 of 6 immunized with rRAP1, and 4 of 6 immunized with RAP2 did not require drug treatment. Two of 6 monkeys immunized with PfRAP1 and 2 with CRL1005 did not require treatment. All groups receiving RAP1, RAP2, or both had a significant decrease in initial parasite multiplication rates and there was a significant negative correlation between anti-RAP2 antibody and multiplication rates. Animals were rechallenged with the homologous parasite 126 days after the first challenge. Of the monkeys that did not require drug treatment after the first challenge, none developed detectable parasitemia following rechallenge.

Comparative gene expression profiling of P. falciparum malaria parasites exposed to three different histone deacetylase inhibitors

Publisher: Public Library of Science (PLoS)

Date: 27-02-2012

DOI: 10.1371/JOURNAL.PONE.0031847

Griffith University

Location: Australia

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QIMR Berghofer Medical Research Institute

Location: Australia

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Heidelberg University

Location: Germany

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Discovery Projects - Grant ID: DP1095425

Start Date: 2010

End Date: 12-2012

Amount: $340,000.00

Funder: Australian Research Council

ARC Future Fellowships - Grant ID: FT0991213

Start Date: 2010

End Date: 12-2014

Amount: $686,400.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP220102618

Start Date: 05-2022

End Date: 05-2025

Amount: $415,495.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100071

Start Date: 03-2012

End Date: 03-2014

Amount: $290,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE230100128

Start Date: 02-2023

End Date: 02-2024

Amount: $1,078,770.00

Funder: Australian Research Council