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Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response (2022)
Journal Article
Alpizer-Sosa, E., Ithnin, N., Wei, W., Pountain, A., Weidt, A., Donachie, A., …Barrett, M. (2022). Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response. PLoS Neglected Tropical Diseases, 16(9), Article e0010779. https://doi.org/10.1371/journal.pntd.0010779

Amphotericin B is increasingly used in treatment of leishmaniasis. Here, fourteen independent lines of Leishmania mexicana and one L. infantum line were selected for resistance to either amphotericin B or the related polyene antimicrobial, nystatin.... Read More about Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response.

Genome deletions to overcome the directed loss of gene function in Leishmania (2022)
Journal Article
Alpizar-Sosa, E., Kumordzi, Y., Wei, W., Whitfield, P., Barrett, M., & Denny, P. (2022). Genome deletions to overcome the directed loss of gene function in Leishmania. Frontiers in Cellular and Infection Microbiology, 12, https://doi.org/10.3389/fcimb.2022.988688

With the global reach of the Neglected Tropical Disease leishmanaisis increasing, coupled with a tiny armoury of therapeutics which all have problems with resistance, cost, toxicity and/or administration, the validation of new drug targets in the cau... Read More about Genome deletions to overcome the directed loss of gene function in Leishmania.

Illuminating Host-Parasite Interaction at the Cellular and Subcellular Levels with Infrared Microspectroscopy (2022)
Journal Article
Elsheikha, H. M., Al-Sandaqchi, A. T., Harun, M. S., Winterton, F., Altharawi, A., Elsaied, N. A., …Chan, K. L. A. (2022). Illuminating Host-Parasite Interaction at the Cellular and Subcellular Levels with Infrared Microspectroscopy. Cells, 11(5), Article 811. https://doi.org/10.3390/cells11050811

Toxoplasma gondii (T. gondii) is an opportunistic protozoan that can cause brain infection and other serious health consequences in immuno-compromised individuals. This parasite has a remarkable ability to cross biological barriers and exploit the ho... Read More about Illuminating Host-Parasite Interaction at the Cellular and Subcellular Levels with Infrared Microspectroscopy.

Transcriptome-Wide Identification of Coding and Noncoding RNA-Binding Proteins Defines the Comprehensive RNA Interactome of Leishmania mexicana (2022)
Journal Article
Kalesh, K., Wei, W., Mantilla, B., Roumeliotis, T., Choudhary, J., & Denny, P. (2022). Transcriptome-Wide Identification of Coding and Noncoding RNA-Binding Proteins Defines the Comprehensive RNA Interactome of Leishmania mexicana. Microbiology Spectrum, 10(1), e02422-21. https://doi.org/10.1128/spectrum.02422-21

Proteomic profiling of RNA-binding proteins in Leishmania is currently limited to polyadenylated mRNA-binding proteins, leaving proteins that interact with nonadenylated RNAs, including noncoding RNAs and pre-mRNAs, unidentified. Using a combination... Read More about Transcriptome-Wide Identification of Coding and Noncoding RNA-Binding Proteins Defines the Comprehensive RNA Interactome of Leishmania mexicana.

The Histidine Ammonia Lyase of Trypanosoma cruzi is Involved in Acidocalcisome Alkalinization and is Essential for Survival under Starvation Conditions (2021)
Journal Article
Mantilla, B., Azevedo, C., Denny, P., Saiardi, A., & Docampo, R. (2021). The Histidine Ammonia Lyase of Trypanosoma cruzi is Involved in Acidocalcisome Alkalinization and is Essential for Survival under Starvation Conditions. mBio, 12(6), https://doi.org/10.1128/mbio.01981-21

Trypanosoma cruzi, the agent of Chagas disease, accumulates polyphosphate (polyP) and Ca2+ inside acidocalcisomes. The alkalinization of this organelle stimulates polyP hydrolysis and Ca2+ release. Here, we report that histidine ammonia lyase (HAL),... Read More about The Histidine Ammonia Lyase of Trypanosoma cruzi is Involved in Acidocalcisome Alkalinization and is Essential for Survival under Starvation Conditions.

Chalcones identify cTXNPx as a potential antileishmanial drug target (2021)
Journal Article
Escrivani, D. O., Charlton, R. L., Caruso, M. B., Burle-Caldas, G. A., Borsodi, M. P. G., Zingali, R. B., …Steel, P. G. (2021). Chalcones identify cTXNPx as a potential antileishmanial drug target. PLoS Neglected Tropical Diseases, 15(11), Article e0009951. https://doi.org/10.1371/journal.pntd.0009951

With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2’,6’-dihydroxy-4’-met... Read More about Chalcones identify cTXNPx as a potential antileishmanial drug target.

Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana (2021)
Journal Article
Karunakaran, K., Sundriyal, S., Perera, H., Cobb, S. L., & Denny, P. W. (2021). Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana. mSystems, https://doi.org/10.1128/msystems.00089-21

Heat shock protein 90 (Hsp90) is a conserved molecular chaperone responsible for the folding and maturation of nascent proteins. Hsp90 is regarded as a master regulator of protein homeostasis in the cell, and its inhibition affects the functions of a... Read More about Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana.

Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase (2020)
Journal Article
Mina, J. G., Charlton, R. L., Alpizar-Sosa, E., Escrivani, D. O., Brown, C., Alqaisi, A., …Steel, P. G. (2021). Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase. ACS Infectious Diseases, 7(1), 47-63. https://doi.org/10.1021/acsinfecdis.0c00546

Current chemotherapeutics for leishmaniasis have multiple deficiencies, and there is a need for new safe, efficacious, and affordable medicines. This study describes a successful drug repurposing approach that identifies the over-the-counter antihist... Read More about Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase.

Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination (2020)
Journal Article
Faridnia, R., Kalani, H., Hezarjaribi, H. Z., Denny, P. W., Rafie, A., Fakhar, M., & Virgilio, S. (2020). Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination. Microbial Pathogenesis, 147, Article 104406. https://doi.org/10.1016/j.micpath.2020.104406

We focused on apoptotic blebs from Leishmania major-infected macrophages as a vaccine for cutaneous leishmaniasis. Apoptosis was induced in L. major-infected J774A.1 cells in order to prepare apoptotic blebs. Test groups of BALB/c mice were immunized... Read More about Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination.

An investigation of the antileishmanial properties of semi-synthetic saponins (2020)
Journal Article
Anderson, O., Beckett, J., Briggs, C., Natrass, L., Cranston, C., Wilkinson, E., …Denny, P. (2020). An investigation of the antileishmanial properties of semi-synthetic saponins. RSC Medicinal Chemistry, 11(7), 833-842. https://doi.org/10.1039/d0md00123f

Leishmaniasis is a neglected tropical disease caused by insect-vector borne protozoan parasites of the, Leishmania species. Whilst infection threatens and affects millions of the global poor, vaccines are absent and drug therapy limited. Extensive ef... Read More about An investigation of the antileishmanial properties of semi-synthetic saponins.

A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation (2019)
Journal Article
Karunakaran, K., & Denny, P. W. (2019). A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation. PLoS Neglected Tropical Diseases, 13(12), Article e0007651. https://doi.org/10.1371/journal.pntd.0007651

Adaptation to starvation is integral to the Leishmania life cycle. The parasite can survive prolonged periods of nutrient deprivation both in vitro and in vivo. The identification of parasite proteins synthesised during starvation is key to unravelli... Read More about A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation.

Mining for natural product antileishmanials in a fungal extract library (2019)
Journal Article
Mbekeani, A., Jones, R., Bassas Llorens, M., Elliot, J., Regnault, C., Barrett, M., …Denny, P. (2019). Mining for natural product antileishmanials in a fungal extract library. International Journal for Parasitology: Drugs and Drug Resistance, 11, 118-128. https://doi.org/10.1016/j.ijpddr.2019.05.003

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private... Read More about Mining for natural product antileishmanials in a fungal extract library.

The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity (2019)
Journal Article
Pinneh, E., Mina, J., Stark, M., Lindell, S., Luemmen, P., Knight, M., …Denny, P. (2019). The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity. Scientific Reports, 9, Article 8083. https://doi.org/10.1038/s41598-019-44544-1

Resistance to 157 different herbicides and 88% of known sites of action has been observed, with many weeds resistant to two or more modes. Coupled with tighter environmental regulation, this demonstrates the need to identify new modes of action and n... Read More about The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity.

Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana (2019)
Journal Article
Pinneh, E., Stoppel, R., Knight, H., Knight, M., Steel, P., & Denny, P. (2019). Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana. PLoS ONE, 14(5), Article e0217087. https://doi.org/10.1371/journal.pone.0217087

This research was undertaken to investigate the global role of the plant inositol phosphorylceramide synthase (IPCS), a non-mammalian enzyme previously shown to be associated with the pathogen response. RNA-Seq analyses demonstrated that over-express... Read More about Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana.

Lytic reactions of drugs with lipid membranes (2018)
Journal Article
Britt, H. M., García-Herrero, C. A., Denny, P. W., Mosely, J. A., & Sanderson, J. M. (2019). Lytic reactions of drugs with lipid membranes. Chemical Science, 10(3), 674-680. https://doi.org/10.1039/c8sc04831b

Propranolol is shown to undergo lipidation reactions in three types of lipid membrane: (1) synthetic single-component glycerophospholipid liposomes; (2) liposomes formed from complex lipid mixtures extracted from E. coli or liver cells; and (3) in ce... Read More about Lytic reactions of drugs with lipid membranes.

Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania (2018)
Journal Article
Trinconi, C. T., Miguel, D. C., Silber, A. M., Brown, C., Mina, J. G., Denny, P. W., …Uliana, S. R. (2018). Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania. International Journal for Parasitology: Drugs and Drug Resistance, 8(3), 475-487. https://doi.org/10.1016/j.ijpddr.2018.10.007

Previous work from our group showed that tamoxifen, an oral drug that has been in use for the treatment of breast cancer for over 40 years, is active both in vitro and in vivo against several species of Leishmania, the etiological agent of leishmania... Read More about Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania.