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1. Discovery of 1,3,4-oxadiazoles with slow-action activity against Plasmodium falciparum malaria parasites

Author

Andrews, Katherine T., Fisher, Gillian M., Firmin, Meaghan, Liepa, Andris J., Wilson, Tony, Gardiner, James, Mohri, Yacine, Debele, Emmanuel, Rai, Anjana, Davey, Andrew K., Masurier, Antoine, Delion, Alix, Mouratidis, Alexandros A., Hutt, Oliver E., Forsyth, Craig M., Burrows, Jeremy N., Ryan, John H., Riches, Andrew G., and Skinner-Adams, Tina S.

Published
2024
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2. That's RAD! Science STEM Books: Survey Results on Adult Perceptions of Benefits and Impacts

Author

Condon, Kathleena, Cross, Megan, Walkden, Heidi, Pendergast, Donna, and Andrews, Katherine T.

Abstract

The need for early engagement in science, technology, engineering, and mathematics (STEM), and representation of role models in STEM careers is of national and international importance. The That's RAD! Science project aims to address these needs through a series of engaging picture books for younger children that feature women in STEM as role models. The goal of this research project was to use a survey tool to gain feedback from adults on their impression of the impacts and benefits on children of the That's RAD! Science books, as well as their perceptions of the benefits of STEM engagement and use of identifiable women in STEM as role models. Participants were sent a set of four That's RAD! Science books for children to engage with and the adult participant then completed an online survey. A total of 83 participants were recruited, with a 61% completion rate for the online survey. Of these, 98% identified as parents/carers. Survey data showed the That's RAD! Science books engaged children and the books are also beneficial to informal hands-on learning processes.

Published
2020

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

Author

Van Voorhis, Wesley C, Adams, John H, Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H, Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T, Avery, Simon V, Avery, Vicky M, Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E, Boyom, Fabrice F, Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R, Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L, Colón-López, Daisy D, Corbett, Yolanda, Crowther, Gregory J, Cowan, Noemi, D'Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L, Du, Alan Y, Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T, Fernández Robledo, José A, Fidock, David A, Florent, Isabelle, Fokou, Patrick VT, Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M, Guha, Rajarshi, Guiguemde, W Armand, Gural, Nil, Guy, R Kiplin, Hansen, Michael AE, Hanson, Kirsten K, Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B, Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A, Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T, Jiang, Rays HY, Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P, Kyle, Dennis E, Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M, Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I, Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, and Maes, Louis

Subjects
Humans, Malaria, Antimalarials, Drug Evaluation, Preclinical, Small Molecule Libraries, Drug Discovery, Neglected Diseases, Datasets as Topic, Drug Evaluation, Preclinical, Virology, Microbiology, Immunology, Medical Microbiology
Abstract

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

Published
2016

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

Author

Andrews, Katherine T., primary, Fisher, Gillian M., additional, Firmin, Meaghan, additional, Liepa, Andris J., additional, Wilson, Tony, additional, Gardiner, James, additional, Mohri, Yacine, additional, Rai, Anjana, additional, Davey, Andrew K., additional, Masurier, Antoine, additional, Delion, Alix, additional, Mouratidis, Alexandos A., additional, Hutt, Oliver, additional, Burrows, Jeremy N., additional, Ryan, John H., additional, Riches, Andrew G., additional, and Skinner-Adams, Tina S., additional

Published
2023
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26. QSAR Classification Models for Prediction of Hydroxamate Histone Deacetylase Inhibitor Activity against Malaria Parasites

Author

Hesping, Eva, primary, Chua, Ming Jang, additional, Pflieger, Marc, additional, Qian, Yunan, additional, Dong, Lilong, additional, Bachu, Prabhakar, additional, Liu, Ligong, additional, Kurz, Thomas, additional, Fisher, Gillian M., additional, Skinner-Adams, Tina S., additional, Reid, Robert C., additional, Fairlie, David P., additional, Andrews, Katherine T., additional, and Gorse, Alain-Dominique J.P., additional

Published
2022
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29. New inhibitors and tools to advance HDAC drug discovery for malaria

Author

Andrews, Katherine T, Skinner-Adams, Tina, Thomas, Kurz, Hesping, Eva M, Andrews, Katherine T, Skinner-Adams, Tina, Thomas, Kurz, and Hesping, Eva M

Abstract

Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Environment and Sc, Science, Environment, Engineering and Technology, Malaria is a leading cause of morbidity and mortality, causing more than 400,000 deaths per year. Malaria is caused by parasites of the Plasmodium genus with most deaths due to P. falciparum infection. The control of malaria is complicated by the lack of a widely effective vaccine, the spread of mosquito resistance to insecticides and Plasmodium parasite resistance to available drugs, including the gold standard artemisinin-combination therapies. Thus, there is an urgent requirement for the development of new antimalarials, in particular those with different modes of action to existing drugs to limit potential problems of cross-resistance. Plasmodium species have a complex lifecycle that includes transmission from the female Anopheles mosquito vector to a human host requiring significant morphological changes. These morphological changes are associated with stage-specific changes in transcription regulated by epigenetic mechanisms. The proteins involved in these processes are potential new therapeutic targets for malaria. This includes histone deacetylases (HDACs), which together with histone acetyltransferases (HATs), are involved in reversible posttranslational acetylation of histone and non-histone proteins, regulating transcription and other cellular processes. To date, over 650 HDAC inhibitors have been investigated for in vitro activity against malaria parasites. Some inhibitors, particularly those with a hydroxamic acid zinc-binding group that targets inhibitors to the HDAC active site, have demonstrated low nM in vitro potency against P. falciparum and selectivity for the parasite over human cells. However, antiplasmodial HDAC inhibitor drug development has been hindered by factors including the lack of recombinant P. falciparum HDACs (only one available and purity is low), the lack of HDAC crystal structures (none available) and low throughput activity assays that are largely indirect measures of HDAC inhibition. Without these tools, mode of action studies

Published
2021

30. Consequences of in vitro hyperoxia on Plasmodium falciparum tolerance to artemisinin

Author

Avery, Vicky M, Andrews, Katherine T, Cheng, Qin, Duffy, Sandra, Avery, Vicky M, Andrews, Katherine T, Cheng, Qin, and Duffy, Sandra

Abstract

Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Environment and Sc, Science, Environment, Engineering and Technology, Plasmodium falciparum is the major causative agent of malaria in man and is responsible for over 400,000 deaths per year, predominantly in Sub-Saharan Africa. P. falciparum exists in many forms within both the human host and mosquito vector. In clinical malaria the parasite resides within the red blood cells of the human host and is transmitted from one host to another through the blood feeding bite of the female Anopheles mosquito. Malaria, as a disease, is completely curable, and many countries have eradicated malaria, including Australia in 1981. However, malaria remains endemic in most poor countries. Overall, both case numbers and mortality rates are decreasing each year, primarily due to improved preventative measures, and importantly the use of artemisinin combination therapies (ACT) employed globally. The chink in the armour of chemotherapeutics currently available for the treatment of malaria is parasite drug resistance. Artemisinin was believed to be the exception, as stable in vitro generated artemisinin resistant parasites proved difficult to obtain. However, in 2007, clinical parasite delayed clearance times were observed for the artemisinin derivative, artesunate, used as a monotherapy in Western Cambodia, the epicentre of anti-malarial drug resistance origins. Standard laboratory drug sensitivity tests did not detect differences in parasite sensitivity between those from patients with or without delayed parasite clearance times. The use of artemisinin derivatives as a combination therapy was advocated, but underlying artemisinin tolerance, or partial resistance originating in Western Cambodia, has resulted in the acquisition of partner drug resistance and ultimately failure of standard 3-day ACT treatment regimens. A single nucleotide polymorphism in a kelch-13 (K13) propeller domain (PF3D7_1343700) was identified through escalating artemisinin drug exposure and recovery in vitro, correlating with extended in vivo parasite clearance times, providing a

Published
2021

35. Identifying new compounds active against Giardia duodenalis

Author

Skinner-Adams, Tina, Andrews, Katherine T, Ryan, John H, Riches, Andrew, Hart, Christopher J, Skinner-Adams, Tina, Andrews, Katherine T, Ryan, John H, Riches, Andrew, and Hart, Christopher J

Abstract

Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Environment and Sc, Science, Environment, Engineering and Technology, Giardia are a genus of enteric pathogens consisting of at least six species (Monis et al. 2009), of which one, Giardia duodenalis, infects humans (Heyworth 2016). In addition to humans, G. duodenalis parasites infect other mammals, which may act as reservoirs for human infection (Traub et al. 2004; Yaoyu and Xiao 2011; Abeywardena et al. 2015; Sroka et al. 2015; Štrkolcová et al. 2015; Heyworth 2016). In humans Giardia infection can be asymptomatic, however all infected hosts shed cysts and can transmit parasites (Oliveira-Arbex et al. 2016; Figgatt et al. 2017). Giardia infection can cause giardiasis, a diarrhoeal disease with a variety of clinical manifestations (Wolfe 1992; Homan and Mank 2001; Sahagún et al. 2008; Nielsen et al. 2014). An estimated 180 million symptomatic human Giardia infections occur every year (Kirk et al. 2015), and treatment is reliant on a small number of chemotherapeutic classes, all of which are associated with liabilities. Liabilities include but are not limited to; poor treatment efficacies, long treatment courses and side-effects which impact compliance (Cina et al. 1996; Wright et al. 2003; Escobedo and Cimerman 2007; Nabarro et al. 2015). Growing parasite resistance to the first-line treatment drugs, the 5-nitroimidazoles, is also a concern (Nabarro et al. 2015). The aim of the current study was to pave the way towards improved treatment options for giardiasis by identifying new lead compounds for drug development, and to further examine the activity of these compounds. To achieve this, a new anti-Giardia activity assay to assess parasite growth in micro-titre plates under microaerobic (3 % O2) conditions was developed. This image-based assay uses bright-field microscopy paired with digital phase-contrast microscopy and supervised machine learning software, PhenoLOGIC and Harmony® (Perkin-Elmer, USA) to differentiate and enumerate parasites. Growth assessment does not require cell-staining or a genetically modified parasite line, th

Published
2020

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

Author

Vu, Hoan, Pedro, Liliana, Mak, Tin, McCormick, Brendan, Rowley, Jessica, Liu, Miaomiao, Di Capua, Angela, Williams-Noonan, Billy, Pham, Ngoc B., Pouwer, Rebecca, Nguyen, Bao, Andrews, Katherine T., Skinner-Adams, Tina, Kim, Jessica, Hol, Wim G. J., Hui, Raymond, Crowther, Gregory J., Van Voorhis, Wesley C., and Quinn, Ronald J.

Subjects
Antimalarials, Biological Products, natural products, native mass spectrometry, target identification, fragments, Plasmodium falciparum, malaria, Drug Evaluation, Preclinical, Protozoan Proteins, Featured Article, Mass Spectrometry, Protein Binding
Abstract

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.

Published
2018

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

Author

Fisher, Gillian M., primary, Cobbold, Simon A., additional, Jezewski, Andrew, additional, Carpenter, Emma F., additional, Arnold, Megan, additional, Cowell, Annie N., additional, Tjhin, Erick T., additional, Saliba, Kevin J., additional, Skinner-Adams, Tina S., additional, Lee, Marcus C. S., additional, Odom John, Audrey, additional, Winzeler, Elizabeth A., additional, McConville, Malcolm J., additional, Poulsen, Sally-Ann, additional, and Andrews, Katherine T., additional

Published
2020
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43. Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

Author

Heffernan, Aaron J., primary, Sime, Fekade B., additional, Sarovich, Derek S., additional, Neely, Michael, additional, Guerra-Valero, Yarmarly, additional, Naicker, Saiyuri, additional, Cottrell, Kyra, additional, Harris, Patrick, additional, Andrews, Katherine T., additional, Ellwood, David, additional, Wallis, Steven C., additional, Lipman, Jeffrey, additional, Grimwood, Keith, additional, and Roberts, Jason A., additional

Published
2020
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