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In situ Product Recovery of Microbially Synthesized Ethyl Acetate from the Exhaust Gas of a Bioreactor by Membrane Technology

Abstract (Expand)

Ethyl acetate is at present exclusively produced from fossil resources. Microbial synthesis of this ester from sugar‐rich waste as an alternative is an aerobic process. Ethyl acetate is highly volatile … and therefore stripped with the exhaust gas from the bioreactor which enables in situ product recovery. Previous research on microbial formation of ethyl acetate has focused on the kinetics of ester synthesis and in part on the ester stripping, while the separation of the ester from the exhaust gas has hardly been investigated. A mixed matrix membrane was developed consisting of Silikalite‐1 embedded in polydimethylsiloxane which was installed in a radial–symmetrical membrane module. Evaluation of the separation of ethyl acetate was based on the analysis of the composition of the feed and retentate gas by mass spectrometry. The separation efficiency of the membrane was first tested with varied flows of artificial exhaust gas, containing defined amounts of ethyl acetate. A model for describing the separation process was parametrized by the measured data and used to design a real separation experiment. Ethyl acetate produced from delactosed whey permeate by Kluyveromyces marxianus DSM 5422 in a stirred bioreactor gassed with 0.5 vvm air was successfully separated from the exhaust gas by membranes; 93.6% of the stripped ester was separated. Liquid ethyl acetate was recovered by cooling the permeate gas to ‒78°C, whereby 99.75% of the condensed organic compounds were ethyl acetate. This study demonstrates for the first time that microbially produced and stripped ethyl acetate can be effectively separated from the exhaust gas of bioreactors by membrane technology to obtain the ester in high yield and purity.

Authors: Andreas Hoffmann, Alexander Franz, Christian Löser, Thomas Hoyer, Marcus Weyd, Thomas Walther

Date Published: 30th Sep 2024

Publication Type: Journal Article

3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies

Abstract

Not specified

Authors: Baptiste Dupouy, Maxime Donzel, Matthieu Roignant, Sarah Charital, Rodrigue Keumoe, Yoshiki Yamaryo-Botté, Alexander Feckler, Mirco Bundschuh, Yann Bordat, Matthias Rottmann, Pascal Mäser, Cyrille Y. Botté, Stéphanie A. Blandin, Sébastien Besteiro, Elisabeth Davioud-Charvet

Date Published: 27th Sep 2024

Publication Type: Journal Article

Abundant clock proteins point to missing molecular regulation in the plant circadian clock

Abstract (Expand)

Understanding the biochemistry behind whole-organism traits such as flowering time is a longstanding challenge, where mathematical models are critical. Very few models of plant gene circuits use the … absolute units required for comparison to biochemical data. We refactor two detailed models of the plant circadian clock from relative to absolute units. Using absolute RNA quantification, a simple model predicted abundant clock protein levels in Arabidopsis thaliana , up to 100,000 proteins per cell. NanoLUC reporter protein fusions validated the predicted levels of clock proteins in vivo . Recalibrating the detailed models to these protein levels estimated their DNA-binding dissociation constants (Kd). We estimate the same Kd from multiple results in vitro , extending the method to any promoter sequence. The detailed models simulated the Kd range estimated from LUX DNA-binding in vitro but departed from the data for CCA1 binding, pointing to further circadian mechanisms. Our analytical and experimental methods should transfer to understand other plant gene regulatory networks, potentially including the natural sequence variation that contributes to evolutionary adaptation.

Authors: Uriel Urquiza-García, Nacho Molina, Karen J. Halliday, Andrew J. Millar

Date Published: 3rd Sep 2024

Publication Type: Journal Article

Effect of Leishmania infantum infection on B cell lymphopoiesis and memory in the bone marrow and spleen.

Abstract (Expand)

Visceral leishmaniasis (VL) is characterized by an uncontrolled infection of internal organs such as the spleen, liver and bone marrow (BM) and can be lethal when left untreated. No effective vaccination … is currently available for humans. The importance of B cells in infection and VL protective immunity has been controversial, with both detrimental and protective effects described. VL infection was found in this study to increase not only all analyzed B cell subsets in the spleen but also the B cell progenitors in the BM. The enhanced B lymphopoiesis aligns with the clinical manifestation of polyclonal hypergammaglobulinemia and the occurrence of autoantibodies. In line with earlier reports, flow cytometric and microscopic examination identified parasite attachment to B cells of the BM and spleen without internalization, and transformation of promastigotes into amastigote morphotypes. The interaction appears independent of IgM expression and is associated with an increased detection of activated lysosomes. Furthermore, the extracellularly attached amastigotes could be efficiently transferred to infect macrophages. The observed interaction underscores the potentially crucial role of B cells during VL infection. Additionally, using immunization against a fluorescent heterologous antigen, it was shown that the infection does not impair immune memory, which is reassuring for vaccination campaigns in VL endemic areas.

Authors: L. Dirkx, M. Loyens, S. I. Van Acker, D. Bulte, M. Claes, M. Radwanska, S. Magez, G. Caljon

Date Published: 31st Aug 2024

Publication Type: Journal Article

Kinetic characterization of two neuraminic acid synthases and evaluation of their application potential

Abstract (Expand)

Neuraminic acid synthases are an important yet underexplored group of enzymes. Thus, in this research, we performed a detailed kinetic and stability analysis and a comparison of previously known … neuraminic acid synthase from Neisseria meningitidis, and a novel enzyme, PNH5, obtained from a metagenomic library. A systematic analysis revealed a high level of similarity of PNH5 to other known neuraminic acid synthases, except for its pH optimum, which was found to be at 5.5 for the novel enzyme. This is the first reported enzyme from this family that prefers an acidic pH value. The effect of different metal cofactors on enzyme activity, i.e. Co2+, Mn2+ and Mg2+, was studied systematically. The kinetics of neuraminic acid synthesis was completely elucidated, and an appropriate kinetic model was proposed. Enzyme stability study revealed that the purified enzyme exhibits changes in its structure during time as observed by differential light scattering, which cause a drop in its activity and protein concentration. The operational enzyme stability for the neuraminic acid synthase from N. meningitidis is excellent, where no activity drop was observed during the batch reactor experiments. In the case of PNH5, some activity drop was observed at higher concentration of substrates. The obtained results present a solid platform for the future application of these enzymes in the synthesis of sialic acids.

Authors: Mehmet Mervan Çakar, Nevena Milčić, Theofania Andreadaki, Simon Charnock, Wolf-Dieter Fessner, Zvjezdana Findrik Blažević

Date Published: 21st Aug 2024

Publication Type: Journal Article

Veterinary perspectives on the urbanization of leishmaniosis in Morocco

Abstract (Expand)

Abstract Background Leishmaniosis caused by Leishmania infantum, L. major and L. tropica is endemic in Morocco. Growing evidence of both human and canine Leishmania infections in urban centres has been …ctions in urban centres has been reported. Since many forms of the disease are zoonotic, veterinarians play an important role in leishmaniosis control by intervening at the parasite host level. This study aimed to bring together One Health principles to connect canine and feline leishmaniosis epidemiology within urban centres of Morocco (Rabat and Fez) and assess the level of awareness of Moroccan veterinarians about facing this threat. Methods A molecular survey was conducted for Leishmania DNA detection in canine (n = 155) and feline (n = 32) whole-blood samples. Three conventional polymerase chain reaction (PCR) protocols were implemented. The first PCR aimed at identifying infected animals by targeting Leishmania spp. kinetoplast minicircle DNA (kDNA). The second and third PCR targeted the Leishmania internal transcribed spacer region (ITS-1) and the Leishmania small subunit ribosomal RNA (SSUrRNA) gene, respectively, aiming at identification of the infecting species after Sanger sequencing-positive amplicons. Total immunoglobulin G (IgG) against Leishmania spp. was evaluated in 125 dogs by enzyme-linked immunosorbent assays (ELISA) using an in-house protocol, including three Leishmania-specific antigens (SPLA, rKDDR and LicTXNPx). Sera from 25 cats were screened for total IgG to Leishmania spp. by an indirect immunofluorescence antibody test (IFAT). An online questionnaire was presented to Moroccan veterinarians addressing their knowledge and practices towards animal leishmaniosis. Results Overall, 19.4% of the dogs tested positive for Leishmania kDNA and ITS-1 and sequencing revealed infection with L. infantum among PCR-positive dogs. These animals presented a wide range of ELISA seropositivity results (16.7%, 34.9% and 51.6%) according to the tested antigens (rKDDR, SPLA and LicTXNPx, respectively). Use of kDNA-PCR revealed 12.5% cats positive to Leishmania spp. otherwise found to be seronegative by IFAT. Conclusions A considerable prevalence of infection was identified in dogs from urban centres of Morocco. Additionally, this is the first report of feline infection with Leishmania spp. in this country and in urban settings. Moroccan veterinarians are aware that animal leishmaniosis is endemic in Morocco, representing a public health threat, and are knowledgeable about canine leishmaniosis diagnosis and treatment. Graphical Abstract

Authors: Clara M. Lima, Maria Bourquia, Abderrahmane Zahri, Nada Haissen, Nuno Santarém, Luís Cardoso, Anabela Cordeiro da Silva

Date Published: 19th Aug 2024

Publication Type: Journal Article

A breath of fresh air: impact of insect-borne protozoan parasites on the respiratory system.

Abstract (Expand)

The protozoan parasites Plasmodium, Leishmania, and Trypanosoma are transmitted by hematophagous insects and cause severe diseases in humans. These infections pose a global threat, particularly in … low-resource settings, and are increasingly extending beyond the current endemic regions. Tropism of parasites is crucial for their development, and recent studies have revealed colonization of noncanonical tissues, aiding their survival and immune evasion. Despite receiving limited attention, cumulative evidence discloses the respiratory system as a significant interface for host-pathogen interactions, influencing the course of (co)infection and disease onset. Due to its pathophysiological and clinical implications, we emphasize that further research is needed to better understand the involvement of the respiratory system and its potential to improve prevention, diagnosis, treatment, and interruption of the chain of transmission.

Authors: S. Araujo, D. Mabille, A. B. Garcia, G. Caljon

Date Published: 9th Aug 2024

Publication Type: Journal Article

N-Pyrazolyl- and N-Triazolylamines and -Ureas as Antileishmanial and Antitrypanosomal Drugs.

Abstract (Expand)

Three types of modifications of antileishmanial pyrazole lead compounds 7 and 8 were conducted to expand understanding of the relationships between structural features and antileishmanial/antitrypanosomal … activity: (1) the pyrazole core was retained or replaced by a 1,2,4-triazole ring; (2) various aryl moieties including 2-fluorophenyl, pyridin-3-yl and pyrazin-2-yl rings were attached at 3-position of the core azole; (3) either arylmethylamino or ureido substituents were introduced at 5-position of the azole core. The synthesis followed established routes starting with esters 9 or 15 and anhydride 21. The synthesized 3-arylpyrazoles and 3-aryl-1,2,4-triazoles had only very low antileishmanial activity. The 2-fluorophenyl-substituted pyrazole 18c revealed the highest antileishmanial activity of this series of compounds, but its IC(50) value (20 muM) still indicates low activity. However, low micromolar antitrypanosomal activity was detected for the pyridin-3-yl-substituted pyrazoles 12b (IC(50)=4.7 muM) and 14a (IC(50)=2.1 muM). Their IC(50) values are comparable with the IC(50) values of the reference compounds benznidazole and nifurtimox. Whereas only low unspecific cytotoxicity at the primary peritoneal mouse macrophages (PMM) was detected, considerable cytotoxicity at MRC-5 human fibroblast cells was found for both pyrazoles 12b an 14a. The activity of pyrazole 12b against T. cruzi is 4-fold higher than its unspecific MRC-5 cytotoxicity.

Authors: T. Winge, L. Imberg, B. Perry, A. Matheeussen, G. Caljon, D. Kalinin, B. Wunsch

Date Published: 1st Aug 2024

Publication Type: Journal Article

The activities of suaveolol and other compounds from Hyptis suaveolens and Momordica charantia against the aetiological agents of African trypanosomiasis, leishmaniasis and malaria

Abstract

Not specified

Authors: Enimie E. Oaikhena, Umar A. Yahaya, Sani M. Abdulsalami, Nkechi L. Egbe, Modupe M. Adeyemi, Marzuq A. Ungogo, Godwin U. Ebiloma, Felix K. Zoiku, Prince A. Fordjour, Hamza A.A. Elati, Neils B. Quashie, John O. Igoli, Alexander I. Gray, Christopher Lawson, Valerie A. Ferro, Harry P. de Koning

Date Published: 1st Aug 2024

Publication Type: Journal Article

Spliced-Leader RNA as a Dynamic Marker for Monitoring Viable Leishmania Parasites During and After Treatment.

Abstract (Expand)

Accurate detection of viable Leishmania parasites is critical for evaluating visceral leishmaniasis (VL) treatment response at an early timepoint. We compared the decay of kinetoplast DNA (kDNA) and … spliced-leader RNA (SL-RNA) in vitro, in vivo, and in a VL patient cohort. An optimized combination of blood preservation and nucleic acid extraction improved efficiency for both targets. SL-RNA degraded more rapidly during treatment than kDNA, and correlated better with microscopic examination. SL-RNA quantitative polymerase chain reaction emerges as a superior method for dynamic monitoring of viable Leishmania parasites. It enables individualized treatment monitoring for improved prognoses and has potential as an early surrogate endpoint in clinical trials.

Authors: R. Hendrickx, R. Melkamu, D. Tadesse, T. Teferi, P. B. Feijens, M. Vleminckx, S. van Henten, F. Alves, T. Shibru, J. van Griensven, G. Caljon, M. Pareyn

Date Published: 25th Jul 2024

Publication Type: Journal Article

Broadening The Substrate Scope of Aldolases Through Metagenomic Enzyme Discovery

Abstract (Expand)

Bio‐processes based on enzymatic catalysis play a major role in the development of green, sustainable processes, and the discovery of new enzymes is key to this approach. In this work, we analysed ten … metagenomes and retrieved 48 genes coding for deoxyribose‐5‐phosphate aldolases (DERAs, EC 4.1.2.4) using a sequence‐based approach. These sequences were recombinantly expressed in Escherichia coli and screened for activity towards a range of aldol additions. Among these, one enzyme, DERA‐61, proved to be particularly interesting and catalysed the aldol addition of furfural or benzaldehyde with acetone, butanone and cyclobutanone with unprecedented activity. The product of these reactions, aldols, can find applications as building blocks in the synthesis of biologically active compounds. Screening was carried out to identify optimized reaction conditions targeting temperature, pH, and salt concentrations. Lastly, the kinetics and the stereochemistry of the products were investigated, revealing that DERA‐61 and other metagenomic DERAs have superior activity and stereoselectivity when they are provided with non‐natural substrates, compared to well‐known DERAs.

Authors: Andrea Rizzo, Maria Carmen Aranda, James Galman, Annette Alcasabas, Akash Pandya, Amin Bornadel, Bruna Costa, Helen C Hailes, John M Ward, Jack W.E. Jeffries, Beatriz Dominguez

Date Published: 2nd Jul 2024

Publication Type: Journal Article

Metronidazole Interaction with Cu(2+) and Zn(2+): Speciation Study in Aqueous Solution and Biological Activity Evaluation.

Abstract (Expand)

Metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol, MNZ) is a well-known and widely used drug for its excellent activity against various anaerobic bacteria and protozoa. The purpose of this study … is to elucidate the ability of MNZ to form metal complexes with Cu(2+) and Zn(2+) and to demonstrate that complexation increases its bioactivity profile against different pathogenic microorganisms. The interaction of MNZ with Cu(2+) and Zn(2+) was investigated in NaCl aqueous solution under different conditions of temperature (15, 25, and 37 degrees C) and ionic strength (0.15, 0.5, and 1 mol L(-1)) by potentiometric and spectrophotometric titrations. The obtained speciation models include two species for the Cu(2+)-containing system, namely, CuL and CuL(2), and three species for the Zn(2+)-containing system, namely, ZnLH, ZnL, and ZnLOH. The formation constants of the species were calculated and their dependence on temperature and ionic strength evaluated. Comparison of the sequestering ability of MNZ under physiological conditions revealed a capacity toward Cu(2+) higher than that toward Zn(2+). A simulation under the same conditions also showed a significant percentage of the Cu(2+)-MNZ species. The biological assessments highlighted that the complexation of MNZ with Cu(2+) has a relevant impact on the potency of the drug against two Trypanosoma spp. (i.e., T. b. brucei and T. b. rhodesiense) and one gram-(-) bacterial species (i.e., Escherichia coli). It is noteworthy that the increased potency upon complexation with Cu(2+) did not result in cytotoxicity against MRC-5 human fetal lung fibroblasts and primary peritoneal mouse macrophages.

Authors: F. Carnamucio, C. Foti, N. Micale, N. Van Pelt, A. Matheeussen, G. Caljon, O. Giuffre

Date Published: 2nd Jul 2024

Publication Type: Journal Article

Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-<i>Trypanosoma brucei</i> Agents

Abstract

Not specified

Authors: Valeria Francesconi, Marco Rizzo, Cecilia Pozzi, Lorenzo Tagliazucchi, Claude U. Konchie Simo, Giulia Saporito, Giacomo Landi, Stefano Mangani, Anna Carbone, Silvia Schenone, Nuno Santarém, Joana Tavares, Anabela Cordeiro-da-Silva, Maria Paola Costi, Michele Tonelli

Date Published: 2nd Jul 2024

Publication Type: Journal Article

In Vivo Bioluminescence Imaging Reveals Differences in Leishmania infantum Parasite Killing Kinetics by Antileishmanial Reference Drugs.

Abstract (Expand)

The bioluminescent Leishmania infantum BALB/c mouse model was used to evaluate the parasiticidal drug action kinetics of the reference drugs miltefosine, paromomycin, sodium stibogluconate, and liposomal … amphotericin B. Infected mice were treated for 5 days starting from 7 days post-infection, and parasite burdens were monitored over time via bioluminescence imaging (BLI). Using nonlinear regression analyses of the BLI signal, the parasite elimination half-life (t(1/2)) in the liver, bone marrow, and whole body was determined and compared for the different treatment regimens. Significant differences in parasiticidal kinetics were recorded. A single intravenous dose of 0.5 mg/kg liposomal amphotericin B was the fastest acting with a t(1/2) of less than 1 day. Intraperitoneal injection of paromomycin at 320 mg/kg for 5 days proved to be the slowest with a t(1/2) of about 5 days in the liver and 16 days in the bone marrow. To conclude, evaluation of the cidal kinetics of the different antileishmanial reference drugs revealed striking differences in their parasite elimination half-lives. This BLI approach also enables an in-depth pharmacodynamic comparison between novel drug leads and may constitute an essential tool for the design of potential drug combinations.

Authors: S. Hendrickx, P. B. Feijens, F. Escudie, E. Chatelain, L. Maes, G. Caljon

Date Published: 14th Jun 2024

Publication Type: Journal Article

The urgent need for designing greener drugs

Abstract

Not specified

Authors: Tomas Brodin, Michael G. Bertram, Kathryn E. Arnold, Alistair B. A. Boxall, Bryan W. Brooks, Daniel Cerveny, Manuela Jörg, Karen A. Kidd, Unax Lertxundi, Jake M. Martin, Lauren T. May, Erin S. McCallum, Marcus Michelangeli, Charles R. Tyler, Bob B. M. Wong, Klaus Kümmerer, Gorka Orive

Date Published: 5th Jun 2024

Publication Type: Journal Article

Novel quinoline derivatives with broad-spectrum antiprotozoal activities.

Abstract (Expand)

Several quinoline derivatives incorporating arylnitro and aminochalcone moieties were synthesized and evaluated in vitro against a broad panel of trypanosomatid protozoan parasites responsible for … sleeping sickness (Trypanosoma brucei rhodesiense), nagana (Trypanosoma brucei brucei), Chagas disease (Trypanosoma cruzi), and leishmaniasis (Leishmania infantum). Several of the compounds demonstrated significant antiprotozoal activity. Specifically, compounds 2c, 2d, and 4i displayed submicromolar activity against T. b. rhodesiense with half-maximal effective concentration (EC(50)) values of 0.68, 0.8, and 0.19 microM, respectively, and with a high selectivity relative to human lung fibroblasts and mouse primary macrophages ( approximately 100-fold). Compounds 2d and 4i also showed considerable activity against T. b. brucei with EC(50) values of 1.4 and 0.4 microM, respectively.

Authors: C. B. Hartman, P. S. Dube, L. J. Legoabe, N. Van Pelt, A. Matheeussen, G. Caljon, R. M. Beteck

Date Published: 3rd Jun 2024

Publication Type: Journal Article

One Health

Abstract

Not specified

Authors: Michael G. Bertram, Maria Paola Costi, Eli S.J. Thoré, Tara Sabo-Attwood, Bryan W. Brooks

Date Published: 1st Jun 2024

Publication Type: Journal Article

Cross-acyloin condensation of aldehydes catalysed by transketolase variants for the synthesis of aliphatic α-hydroxyketones

Abstract (Expand)

We described a strategy for the enzymatic synthesis of 1-deoxy and 1,2-deoxyketoses from the aliphatic α-ketoacids, pyruvate and 2-oxobutyrate, as donors and natural aldoses of variable chain length … as acceptors, catalyzed by thermostable transketolase variants from Geobacillus stearothermophilus (TKgst). Analytical studies have been carried out on a panel of TKgst variants with the appropriate substrates allowing to select the best combinations and to apply it to the preparative scale synthesis of 1-deoxy and 1,2-deoxyketoses obtained with good to excellent isolated yields (61%–86%). To optimize the strategy, and as a proof of principle, the α-ketoacids pyruvate and 2-oxobutyrate were generated in situ from the corresponding d-amino acids d-alanine and d-homoalanine respectively, using a thermostable d-amino acid oxidase dAAO4536 that was selected from a screening of 55 putative DAAOs provided by Prozomix Limited. Hence, a one-pot one step procedure was performed at 50°C by coupling dAAO4536 and the best TKgst variant H102L/L118I/ H474S in the presence of d-alanine or d-homoalanine as α-ketoacids precursors and d-erythrose as acceptor substrate. The corresponding 1-deoxy and 1,2-dideoxyketoses were isolated with good yields (64% and 72% respectively, out of two steps)

Editor:

Date Published: 30th May 2024

Publication Type: Journal Article

Proteomic Profiling of Antimalarial Plasmodione Using 3‐Benz(o)ylmenadione Affinity‐Based Probes

Abstract (Expand)

AbstractUnderstanding the mechanisms of drug action in malarial parasites is crucial for the development of new drugs to combat infection and to counteract drug resistance. Proteomics is a widely used … approach to study host‐pathogen systems and to identify drug protein targets. Plasmodione is an antiplasmodial early‐lead drug exerting potent activities against young asexual and sexual blood stages in vitro with low toxicity to host cells. To elucidate its molecular mechanisms, an affinity‐based protein profiling (AfBPP) approach was applied to yeast and P. falciparum proteomes. New (pro‐) AfBPP probes based on the 3‐benz(o)yl‐6‐fluoro‐menadione scaffold were synthesized. With optimized conditions of both photoaffinity labeling and click reaction steps, the AfBPP protocol was then applied to a yeast proteome, yielding 11 putative drug‐protein targets. Among these, we found four proteins associated with oxidoreductase activities, the hypothesized type of targets for plasmodione and its metabolites, and other proteins associated with the mitochondria. In Plasmodium parasites, the MS analysis revealed 44 potential plasmodione targets that need to be validated in further studies. Finally, the localization of a 3‐benzyl‐6‐fluoromenadione AfBPP probe was studied in the subcellular structures of the parasite at the trophozoite stage.

Authors: Ilaria Iacobucci, Vittoria Monaco, Agnès Hovasse, Baptiste Dupouy, Rodrigue Keumoe, Bogdan Cichocki, Mourad Elhabiri, Brigitte Meunier, Jean‐Marc Strub, Maria Monti, Sarah Cianférani, Stéphanie A. Blandin, Christine Schaeffer‐Reiss, Elisabeth Davioud‐Charvet

Date Published: 28th May 2024

Publication Type: Journal Article

N(6)-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model.

Abstract (Expand)

Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. … Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-beta-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg(-1), intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg(-1), while the combination (10 + 40 mg kg(-1) of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.

Authors: C. Present, R. D. Girao, C. Lin, G. Caljon, S. Van Calenbergh, O. Moreira, L. A. S. Ruivo, M. M. Batista, R. Azevedo, D. D. G. J. Batista, M. N. C. Soeiro

Date Published: 17th May 2024

Publication Type: Journal Article

Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents

Abstract

Not specified

Authors: Alexandra Ioana Corfu, Nuno Santarem, Sara Luelmo, Gaia Mazza, Alessandro Greco, Alessandra Altomare, Giulio Ferrario, Giulia Nasta, Oliver Keminer, Giancarlo Aldini, Lucia Tamborini, Nicoletta Basilico, Silvia Parapini, Sheraz Gul, Anabela Cordeiro-da-Silva, Paola Conti, Chiara Borsari

Date Published: 8th May 2024

Publication Type: Journal Article

Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites.

Abstract (Expand)

Addressing the challenges of quiescence and post-treatment relapse is of utmost importance in the microbiology field. This study shows that Leishmania infantum and L. donovani parasites rapidly enter … into quiescence after an estimated 2-3 divisions in both human and mouse bone marrow stem cells. Interestingly, this behavior is not observed in macrophages, which are the primary host cells of the Leishmania parasite. Transcriptional comparison of the quiescent and non-quiescent metabolic states confirmed the overall decrease of gene expression as a hallmark of quiescence. Quiescent amastigotes display a reduced size and signs of a rapid evolutionary adaptation response with genetic alterations. Our study provides further evidence that this quiescent state significantly enhances resistance to treatment. Moreover, transitioning through quiescence is highly compatible with sand fly transmission and increases the potential of parasites to infect cells. Collectively, this work identified stem cells in the bone marrow as a niche where Leishmania quiescence occurs, with important implications for antiparasitic treatment and acquisition of virulence traits.

Authors: L. Dirkx, S. I. Van Acker, Y. Nicolaes, J. L. R. Cunha, R. Ahmad, R. Hendrickx, B. Caljon, H. Imamura, D. G. Ebo, D. C. Jeffares, Y. G. Sterckx, L. Maes, S. Hendrickx, G. Caljon

Date Published: 6th May 2024

Publication Type: Journal Article

Bayesian modelling of time series data (BayModTS)—a FAIR workflow to process sparse and highly variable data

Abstract (Expand)

Abstract Motivation Systems biology aims to better understand living systems through mathematical modelling of experimental and clinical data. A pervasive challenge in quantitative dynamical modelling …vasive challenge in quantitative dynamical modelling is the integration of time series measurements, which often have high variability and low sampling resolution. Approaches are required to utilize such information while consistently handling uncertainties. Results We present BayModTS (Bayesian modelling of time series data), a new FAIR (findable, accessible, interoperable, and reusable) workflow for processing and analysing sparse and highly variable time series data. BayModTS consistently transfers uncertainties from data to model predictions, including process knowledge via parameterized models. Further, credible differences in the dynamics of different conditions can be identified by filtering noise. To demonstrate the power and versatility of BayModTS, we applied it to three hepatic datasets gathered from three different species and with different measurement techniques: (i) blood perfusion measurements by magnetic resonance imaging in rat livers after portal vein ligation, (ii) pharmacokinetic time series of different drugs in normal and steatotic mice, and (iii) CT-based volumetric assessment of human liver remnants after clinical liver resection. Availability and implementation The BayModTS codebase is available on GitHub at https://github.com/Systems-Theory-in-Systems-Biology/BayModTS. The repository contains a Python script for the executable BayModTS workflow and a widely applicable SBML (systems biology markup language) model for retarded transient functions. In addition, all examples from the paper are included in the repository. Data and code of the application examples are stored on DaRUS: https://doi.org/10.18419/darus-3876. The raw MRI ROI voxel data were uploaded to DaRUS: https://doi.org/10.18419/darus-3878. The steatosis metabolite data are published on FairdomHub: 10.15490/fairdomhub.1.study.1070.1.

Authors: Sebastian Höpfl, Mohamed Albadry, Uta Dahmen, Karl-Heinz Herrmann, Eva Marie Kindler, Matthias König, Jürgen Rainer Reichenbach, Hans-Michael Tautenhahn, Weiwei Wei, Wan-Ting Zhao, Nicole Erika Radde

Date Published: 1st May 2024

Publication Type: Journal Article

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging

Abstract

Not specified

Authors: Nathan Trometer, Jérémy Pecourneau, Liwen Feng, José A. Navarro-Huerta, Danielle Lazarin-Bidóia, Sueli de Oliveira Silva Lautenschlager, Louis Maes, Amanda Fortes Francisco, John M. Kelly, Brigitte Meunier, Monica Cal, Pascal Mäser, Marcel Kaiser, Elisabeth Davioud-Charvet

Date Published: 12th Apr 2024

Publication Type: Journal Article

Chemoselective Synthesis and Anti-Kinetoplastidal Properties of 2,6-Diaryl-4H-tetrahydro-thiopyran-4-one S-Oxides: Their Interplay in a Cascade of Redox Reactions from Diarylideneacetones

Abstract (Expand)

2,6-Diaryl-4H-tetrahydro-thiopyran-4-ones and corresponding sulfoxide and sulfone derivatives were designed to lower the major toxicity of their parent anti-kinetoplatidal diarylideneacetones through … a prodrug effect. Novel diastereoselective methodologies were developed and generalized from diarylideneacetones and 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones to allow the introduction of a wide substitution profile and to prepare the related S-oxides. The in vitro biological activity and selectivity of diarylideneacetones, 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones, and their S-sulfoxide and sulfone metabolites were evaluated against Trypanosoma brucei brucei, Trypanosoma cruzi, and various Leishmania species in comparison with their cytotoxicity against human fibroblasts hMRC-5. The data revealed that the sulfides, sulfoxides, and sulfones, in which the Michael acceptor sites are temporarily masked, are less toxic against mammal cells while the anti-trypanosomal potency was maintained against T. b. brucei, T. cruzi, L. infantum, and L. donovani, thus confirming the validity of the prodrug strategy. The mechanism of action is proposed to be due to the involvement of diarylideneacetones in cascades of redox reactions involving the trypanothione system. After Michael addition of the dithiol to the double bonds, resulting in an elongated polymer, the latter—upon S-oxidation, followed by syn-eliminations—fragments, under continuous release of reactive oxygen species and sulfenic/sulfonic species, causing the death of the trypanosomal parasites in the micromolar or submicromolar range with high selectivity indexes.

Authors: Thibault Gendron, Don Antoine Lanfranchi, Nicole I. Wenzel, Hripsimée Kessedjian, Beate Jannack, Louis Maes, Sandrine Cojean, Thomas J. J. Müller, Philippe M. Loiseau, Elisabeth Davioud-Charvet

Date Published: 4th Apr 2024

Publication Type: Journal Article

A comparison between different human hepatocyte models reveals profound differences in net glucose production, lipid composition and metabolism in vitro.

Abstract (Expand)

Hepatocytes are responsible for maintaining a stable blood glucose concentration during periods of nutrient scarcity. The breakdown of glycogen and de novo synthesis of glucose are crucial metabolic … pathways deeply interlinked with lipid metabolism. Alterations in these pathways are often associated with metabolic diseases with serious clinical implications. Studying energy metabolism in human cells is challenging. Primary hepatocytes are still considered the golden standard for in vitro studies and have been instrumental in elucidating key aspects of energy metabolism found in vivo. As a result of several limitations posed by using primary cells, a multitude of alternative hepatocyte cellular models emerged as potential substitutes. Yet, there remains a lack of clarity regarding the precise applications for which these models accurately reflect the metabolic competence of primary hepatocytes. In this study, we compared primary hepatocytes, stem cell-derived hepatocytes, adult donor-derived liver organoids, immortalized Upcyte-hepatocytes and the hepatoma cell line HepG2s in their response to a glucose production challenge. We observed the highest net glucose production in primary hepatocytes, followed by organoids, stem-cell derived hepatocytes, Upcyte-hepatocytes and HepG2s. Glucogenic gene induction was observed in all tested models, as indicated by an increase in G6PC and PCK1 expression. Lipidomic analysis revealed considerable differences across the models, with organoids showing the closest similarity to primary hepatocytes in the common lipidome, comprising 347 lipid species across 19 classes. Changes in lipid profiles as a result of the glucose production challenge showed a variety of, and in some cases opposite, trends when compared to primary hepatocytes.

Authors: F. Bonanini, M. Singh, H. Yang, D. Kurek, A. C. Harms, A. Mardinoglu, T. Hankemeier

Date Published: 1st Apr 2024

Publication Type: Journal Article

Assessing Environmental Risks during the Drug Development Process for Parasitic Vector-Borne Diseases: A Critical Reflection

Abstract

Not specified

Authors: Kayhan Ilbeigi, Carlos Barata, João Barbosa, Michael G. Bertram, Guy Caljon, Maria Paola Costi, Alexandra Kroll, Luigi Margiotta-Casaluci, Eli S.J. Thoré, Mirco Bundschuh

Date Published: 27th Mar 2024

Publication Type: Journal Article

Q586B2 is a crucial virulence factor during the early stages of Trypanosoma brucei infection that is conserved amongst trypanosomatids

Abstract (Expand)

AbstractHuman African trypanosomiasis or sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, is characterized by the manipulation of the host’s immune response to ensure parasite … invasion and persistence. Uncovering key molecules that support parasite establishment is a prerequisite to interfere with this process. We identified Q586B2 as a T. brucei protein that induces IL-10 in myeloid cells, which promotes parasite infection invasiveness. Q586B2 is expressed during all T. brucei life stages and is conserved in all Trypanosomatidae. Deleting the Q586B2-encoding Tb927.6.4140 gene in T. brucei results in a decreased peak parasitemia and prolonged survival, without affecting parasite fitness in vitro, yet promoting short stumpy differentiation in vivo. Accordingly, neutralization of Q586B2 with newly generated nanobodies could hamper myeloid-derived IL-10 production and reduce parasitemia. In addition, immunization with Q586B2 delays mortality upon a challenge with various trypanosomes, including Trypanosoma cruzi. Collectively, we uncovered a conserved protein playing an important regulatory role in Trypanosomatid infection establishment.

Authors: Benoit Stijlemans, Patrick De Baetselier, Inge Van Molle, Laurence Lecordier, Erika Hendrickx, Ema Romão, Cécile Vincke, Wendy Baetens, Steve Schoonooghe, Gholamreza Hassanzadeh-Ghassabeh, Hannelie Korf, Marie Wallays, Joar E. Pinto Torres, David Perez-Morga, Lea Brys, Oscar Campetella, María S. Leguizamón, Mathieu Claes, Sarah Hendrickx, Dorien Mabille, Guy Caljon, Han Remaut, Kim Roelants, Stefan Magez, Jo A. Van Ginderachter, Carl De Trez

Date Published: 27th Feb 2024

Publication Type: Journal Article

Kinetic modeling identifies targets for engineering improved photosynthetic efficiency in potato (Solanum tuberosum cv. Solara).

Abstract (Expand)

Potato (Solanum tuberosum) is a significant non-grain food crop in terms of global production. However, its yield potential might be raised by identifying means to release bottlenecks within photosynthetic … metabolism, from the capture of solar energy to the synthesis of carbohydrates. Recently, engineered increases in photosynthetic rates in other crops have been directly related to increased yield - how might such increases be achieved in potato? To answer this question, we derived the photosynthetic parameters V(cmax) and J(max) to calibrate a kinetic model of leaf metabolism (e-Photosynthesis) for potato. This model was then used to simulate the impact of manipulating the expression of genes and their protein products on carbon assimilation rates in silico through optimizing resource investment among 23 photosynthetic enzymes, predicting increases in photosynthetic CO(2) uptake of up to 67%. However, this number of manipulations would not be practical with current technologies. Given a limited practical number of manipulations, the optimization indicated that an increase in amounts of three enzymes - Rubisco, FBP aldolase, and SBPase - would increase net assimilation. Increasing these alone to the levels predicted necessary for optimization increased photosynthetic rate by 28% in potato.

Authors: S. Vijayakumar, Y. Wang, G. Lehretz, S. Taylor, E. Carmo-Silva, S. Long

Date Published: 30th Jan 2024

Publication Type: Journal Article

Chelation of Mitochondrial Iron as an Antiparasitic Strategy

Abstract

Not specified

Authors: Dominik Arbon, Jan Mach, Aneta Čadková, Anna Sipkova, Jan Stursa, Kristýna Klanicová, Marta Machado, Markus Ganter, Viktoriya Levytska, Daniel Sojka, Jaroslav Truksa, Lukáš Werner, Robert Sutak

Date Published: 30th Jan 2024

Publication Type: Journal Article

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