Veterinary Biosciences - Research Publications

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    Advances in the discovery and development of anthelmintics by harnessing natural product scaffolds
    Herath, HMPD ; Taki, AC ; Sleebs, BE ; Hofmann, A ; Nguyen, N ; Preston, S ; Davis, RA ; Jabbar, A ; Gasser, RB ; Rollinson, D ; Stothard, JR (ELSEVIER ACADEMIC PRESS INC, 2021-01-01)
    Widespread resistance to currently-used anthelmintics represents a major obstacle to controlling parasitic nematodes of livestock animals. Given the reliance on anthelmintics in many control regimens, there is a need for the continued discovery and development of new nematocides. Enabling such a focus are: (i) the major chemical diversity of natural products; (ii) the availability of curated, drug-like extract-, fraction- and/or compound-libraries from natural sources; (iii) the utility and practicality of well-established whole-worm bioassays for Haemonchus contortus-an important parasitic nematodes of livestock-to screen natural product libraries; and (iv) the availability of advanced chromatographic (HPLC), spectroscopic (NMR) and spectrometric (MS) techniques for bioassay-guided fractionation and structural elucidation. This context provides a sound basis for the identification and characterisation of anthelmintic candidates from natural sources. This chapter provides a background on the importance and impact of helminth infections/diseases, parasite control and aspects of drug discovery, and reviews recent work focused on (i) screening well-defined compound libraries to establish the methods needed for large-scale screening of natural extract libraries; (ii) discovering plant and marine extracts with nematocidal or nematostatic activity, and purifying bioactive compounds and assessing their potential for further development; and (iii) synthesising analogues of selected purified natural compounds for the identification of possible 'lead' candidates. The chapter describes some lessons learned from this work and proposes future areas of focus for drug discovery. Collectively, the findings from this recent work show potential for selected natural product scaffolds as candidates for future development. Developing such candidates via future chemical optimisation, efficacy and safety evaluations, broad spectrum activity assessments, and target identification represents an exciting prospect and, if successful, could pave the way to subsequent pre-clinical and clinical evaluations.
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    Ticks and tick-borne diseases of bovines in a smallholder livestock context: The Pakistani example
    Ghafar, A ; Gasser, RB ; Abbas, T ; Rehman, A ; Gauci, CG ; Jabbar, A ; Rollinson, D ; Stothard, R (ELSEVIER ACADEMIC PRESS INC, 2021-01-01)
    Ticks and tick-borne diseases (TTBDs) substantially affect the health and production of ruminants, particularly in resource-poor, small-scale farming systems worldwide. However, to date, there has been no critical appraisal of the current state of knowledge of TTBDs in such farming systems. In this article, we systematically reviewed the situation in Pakistan-as an example of a country that is highly reliant on agriculture to sustain its economy, particularly smallholder livestock farms, which are continually faced with challenges associated with TTBDs. The main aims of this review were to gain improved insights into the current status of TTBDs in small-scale farming systems, and to identify knowledge gaps, through the systematic evaluation of published literature on this topic from Pakistan, and to recommend future research directions. We searched publicly available literature from three databases (i.e. Web of Science, Google Scholar, and PubMed) on bovine TTBDs in Pakistan. Of 11,224 published studies identified, 185 were eligible for inclusion; these studies were published between August 1947 and June 2021. A critical analysis of these 185 studies revealed that the diagnosis of ticks and tick-borne pathogens (TBPs) in Pakistan has been based largely on the use of traditional methods (i.e. 'morpho-taxonomy'). At least 54 species of tick have been recorded, most of which belong to the genera Haemaphysalis, Hyalomma and Rhipicephalus. The prevalence of ticks was higher, particularly in young, exotic and crossbred female cattle, during the summer season. Major TBPs include species of Anaplasma, Babesia and Theileria, with prevalences being higher in cattle than buffaloes. Additionally, pathogens of zoonotic potential, including species of Anaplasma, Borrelia, the Crimean-Congo haemorrhagic fever virus, Coxiella, Ehrlichia and Rickettsia, have been recorded in both tick and bovine populations. Information on risk factors, spatial-temporal distribution, genetic diversity, and control of ticks and TBPs is limited, the vector potential of ticks and the distribution patterns of ticks and TBPs in relation to climate remains largely unexplored. Future research should focus on addressing these knowledge gaps and the key challenges of poverty, food security and disease outbreaks in a small-scale livestock farming context in order to provide sustainable, environment-friendly control measures for TTBDs.
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    Impact of climate change on tick-borne diseases of livestock in Pakistan – looking ahead
    Ghafar, A ; Gasser, R ; Jabbar, A ; Nuttal, P (CABI, 2022)
    This expert opinion summarizes the current status of ticks and tick-borne diseases of ruminants in Pakistan. It also assesses the evidence of climate change and its likely impact on the abundance and distribution of ticks and the prevalence and intensity of tick-borne diseases affecting livestock in the country.
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    Whole-organism phenotypic screening methods used in early-phase anthelmintic drug discovery
    Herath, HMPD ; Taki, AC ; Rostami, A ; Jabbar, A ; Keiser, J ; Geary, TG ; Gasser, RB (PERGAMON-ELSEVIER SCIENCE LTD, 2022-07-01)
    Diseases caused by parasitic helminths (worms) represent a major global health burden in both humans and animals. As vaccines against helminths have yet to achieve a prominent role in worm control, anthelmintics are the primary tool to limit production losses and disease due to helminth infections in both human and veterinary medicine. However, the excessive and often uncontrolled use of these drugs has led to widespread anthelmintic resistance in these worms - particularly of animals - to almost all commercially available anthelmintics, severely compromising control. Thus, there is a major demand for the discovery and development of new classes of anthelmintics. A key component of the discovery process is screening libraries of compounds for anthelmintic activity. Given the need for, and major interest by the pharmaceutical industry in, novel anthelmintics, we considered it both timely and appropriate to re-examine screening methods used for anthelmintic discovery. Thus, we reviewed current literature (1977-2021) on whole-worm phenotypic screening assays developed and used in academic laboratories, with a particular focus on those employed to discover nematocides. This review reveals that at least 50 distinct phenotypic assays with low-, medium- or high-throughput capacity were developed over this period, with more recently developed methods being quantitative, semi-automated and higher throughput. The main features assessed or measured in these assays include worm motility, growth/development, morphological changes, viability/lethality, pharyngeal pumping, egg hatching, larval migration, CO2- or ATP-production and/or enzyme activity. Recent progress in assay development has led to the routine application of practical, cost-effective, medium- to high-throughput whole-worm screening assays in academic or public-private partnership (PPP) contexts, and major potential for novel high-content, high-throughput platforms in the near future. Complementing this progress are major advances in the molecular data sciences, computational biology and informatics, which are likely to further enable and accelerate anthelmintic drug discovery and development.
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    A High-Throughput Phenotypic Screen of the 'Pandemic Response Box' Identifies a Quinoline Derivative with Significant Anthelmintic Activity
    Shanley, HT ; Taki, AC ; Byrne, JJ ; Jabbar, A ; Wells, TNC ; Samby, K ; Boag, PR ; Nguyen, N ; Sleebs, BE ; Gasser, RB (MDPI, 2022-02-01)
    Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including Haemonchus contortus, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread resistance to these compounds in nematodes, such that there is a need for new anthelmintics with distinctive mechanisms of action. With a focus on discovering new anthelmintic entities, we screened 400 chemically diverse compounds within the 'Pandemic Response Box' (from Medicines for Malaria Venture, MMV) for activity against H. contortus and its free-living relative, Caenorhabditis elegans-a model organism. Using established phenotypic assays, test compounds were evaluated in vitro for their ability to inhibit the motility and/or development of H. contortus and C. elegans. Dose-response evaluations identified a compound, MMV1581032, that significantly the motility of H. contortus larvae (IC50 = 3.4 ± 1.1 μM) and young adults of C. elegans (IC50 = 7.1 ± 4.6 μM), and the development of H. contortus larvae (IC50 = 2.2 ± 0.7 μM). The favourable characteristics of MMV1581032, such as suitable physicochemical properties and an efficient, cost-effective pathway to analogue synthesis, indicates a promising candidate for further evaluation as a nematocide. Future work will focus on a structure-activity relationship investigation of this chemical scaffold, a toxicity assessment of potent analogues and a mechanism/mode of action investigation.
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    Chromosome-scale Echinococcus granulosus (genotype G1) genome reveals the Eg95 gene family and conservation of the EG95-vaccine molecule
    Korhonen, PK ; Kinkar, L ; Young, ND ; Cai, H ; Lightowlers, MW ; Gauci, C ; Jabbar, A ; Chang, BCH ; Wang, T ; Hofmann, A ; Koehler, A ; Li, J ; Li, J ; Wang, D ; Yin, J ; Yang, H ; Jenkins, DJ ; Saarma, U ; Laurimae, T ; Rostami-Nejad, M ; Irshadullah, M ; Mirhendi, H ; Sharbatkhori, M ; Ponce-Gordo, F ; Simsek, S ; Casulli, A ; Zait, H ; Atoyan, H ; de la Rue, ML ; Romig, T ; Wassermann, M ; Aghayan, SA ; Gevorgyan, H ; Yang, B ; Gasser, RB (NATURE PORTFOLIO, 2022-03-03)
    Cystic echinococcosis is a socioeconomically important parasitic disease caused by the larval stage of the canid tapeworm Echinococcus granulosus, afflicting millions of humans and animals worldwide. The development of a vaccine (called EG95) has been the most notable translational advance in the fight against this disease in animals. However, almost nothing is known about the genomic organisation/location of the family of genes encoding EG95 and related molecules, the extent of their conservation or their functions. The lack of a complete reference genome for E. granulosus genotype G1 has been a major obstacle to addressing these areas. Here, we assembled a chromosomal-scale genome for this genotype by scaffolding to a high quality genome for the congener E. multilocularis, localised Eg95 gene family members in this genome, and evaluated the conservation of the EG95 vaccine molecule. These results have marked implications for future explorations of aspects such as developmentally-regulated gene transcription/expression (using replicate samples) for all E. granulosus stages; structural and functional roles of non-coding genome regions; molecular 'cross-talk' between oncosphere and the immune system; and defining the precise function(s) of EG95. Applied aspects should include developing improved tools for the diagnosis and chemotherapy of cystic echinococcosis of humans.
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    Dysidenin from the Marine Sponge Citronia sp. Affects the Motility and Morphology of Haemonchus contortus Larvae In Vitro
    Ramage, KS ; Taki, AC ; Lum, KY ; Hayes, S ; Byrne, JJ ; Wang, T ; Hofmann, A ; Ekins, MG ; White, JM ; Jabbar, A ; Davis, RA ; Gasser, RB (MDPI, 2021-12-01)
    High-throughput screening of the NatureBank marine extract library (n = 7616) using a phenotypic assay for the parasitic nematode Haemonchus contortus identified an active extract derived from the Australian marine sponge Citronia sp. Bioassay-guided fractionation of the CH2Cl2/MeOH extract from Citronia sp. resulted in the purification of two known hexachlorinated peptides, dysidenin (1) and dysideathiazole (2). Compound 1 inhibited the growth/development of H. contortus larvae and induced multiple phenotypic changes, including a lethal evisceration (Evi) phenotype and/or somatic cell and tissue destruction. This is the first report of anthelmintic activity for these rare and unique polychlorinated peptides.
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    Phylogenetic relationships of the nematode subfamily Phascolostrongylinae from macropodid and vombatid marsupials inferred using mitochondrial protein sequence data
    Sukee, T ; Beveridge, I ; Koehler, A ; Hall, R ; Gasser, RB ; Jabbar, A (BMC, 2021-10-09)
    BACKGROUND: The subfamily Phascolostrongylinae (Superfamily Strongyloidea) comprises nematodes that are parasitic in the gastrointestinal tracts of macropodid (Family Macropodidae) and vombatid (Family Vombatidae) marsupials. Currently, nine genera and 20 species have been attributed to the subfamily Phascolostrongylinae. Previous studies using sequence data sets for the internal transcribed spacers (ITS) of nuclear ribosomal DNA showed conflicting topologies between the Phascolostrongylinae and related subfamilies. Therefore, the aim of this study was to validate the phylogenetic relationships within the Phascolostrongylinae and its relationship with the families Chabertiidae and Strongylidae using mitochondrial amino acid sequences. METHODS: The sequences of all 12 mitochondrial protein-coding genes were obtained by next-generation sequencing of individual adult nematodes (n = 8) representing members of the Phascolostrongylinae. These sequences were conceptually translated and the phylogenetic relationships within the Phascolostrongylinae and its relationship with the families Chabertiidae and Strongylidae were inferred from aligned, concatenated amino acid sequence data sets. RESULTS: Within the Phascolostrongylinae, the wombat-specific genera grouped separately from the genera occurring in macropods. Two of the phascolostrongyline tribes were monophyletic, including Phascolostrongylinea and Hypodontinea, whereas the tribe Macropostrongyloidinea was paraphyletic. The tribe Phascolostrongylinea occurring in wombats was closely related to Oesophagostomum spp., also from the family Chabertiidae, which formed a sister relationship with the Phascolostrongylinae. CONCLUSION: The current phylogenetic relationship within the subfamily Phascolostrongylinae supports findings from a previous study based on ITS sequence data. This study contributes also to the understanding of the phylogenetic position of the subfamily Phascolostrongylinae within the Chabertiidae. Future studies investigating the relationships between the Phascolostrongylinae and Cloacininae from macropodid marsupials may advance our knowledge of the phylogeny of strongyloid nematodes in marsupials.
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    High Throughput Screening of the NatureBank 'Marine Collection' in a Haemonchus Bioassay Identifies Anthelmintic Activity in Extracts from a Range of Sponges from Australian Waters
    Taki, AC ; Byrne, JJ ; Jabbar, A ; Lum, KY ; Hayes, S ; Addison, RS ; Ramage, KS ; Hofmann, A ; Ekins, MG ; Wang, T ; Chang, BCH ; Davis, RA ; Gasser, RB (MDPI, 2021-10-01)
    Widespread resistance in parasitic nematodes to most classes of anthelmintic drugs demands the discovery and development of novel compounds with distinct mechanisms of action to complement strategic or integrated parasite control programs. Products from nature-which assume a diverse 'chemical space'-have significant potential as a source of anthelmintic compounds. In the present study, we screened a collection of extracts (n = 7616) derived from marine invertebrates sampled from Australian waters in a high throughput bioassay for in vitro anti-parasitic activity against the barber's pole worm (Haemonchus contortus)-an economically important parasitic nematode of livestock animals. In this high throughput screen (HTS), we identified 58 active extracts that reduced larval motility by ≥70% (at 90 h), equating to an overall 'hit rate' of ~0.8%. Of these 58 extracts, 16 also inhibited larval development by ≥80% (at 168 h) and/or induced 'non-wild-type' (abnormal) larval phenotypes with reference to 'wild-type' (normal) larvae not exposed to extract (negative controls). Most active extracts (54 of 58) originated from sponges, three from chordates (tunicates) and one from a coral; these extracts represented 37 distinct species/taxa of 23 families. An analysis of samples by 1H NMR fingerprinting was utilised to dereplicate hits and to prioritise a set of 29 sponge samples for future chemical investigation. Overall, these results indicate that a range of sponge species from Australian waters represents a rich source of natural compounds with nematocidal or nematostatic properties. Our plan now is to focus on in-depth chemical investigations of the sample set prioritised herein.
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    Practical High-Throughput Method to Screen Compounds for Anthelmintic Activity against Caenorhabditis elegans
    Taki, AC ; Byrne, JJ ; Boag, PR ; Jabbar, A ; Gasser, RB (MDPI, 2021-07-01)
    In the present study, we established a practical and cost-effective high throughput screening assay, which relies on the measurement of the motility of Caenorhabditis elegans by infrared light-interference. Using this assay, we screened 14,400 small molecules from the "HitFinder" library (Maybridge), achieving a hit rate of 0.3%. We identified small molecules that reproducibly inhibited the motility of C. elegans (young adults) and assessed dose relationships for a subset of compounds. Future work will critically evaluate the potential of some of these hits as candidates for subsequent optimisation or repurposing as nematocides or nematostats. This high throughput screening assay has the advantage over many previous assays in that it is cost- and time-effective to carry out and achieves a markedly higher throughput (~10,000 compounds per week); therefore, it is suited to the screening of libraries of tens to hundreds of thousands of compounds for subsequent evaluation and development. The present phenotypic whole-worm assay should be readily adaptable to a range of socioeconomically important parasitic nematodes of humans and animals, depending on their dimensions and motility characteristics in vitro, for the discovery of new anthelmintic candidates. This focus is particularly important, given the widespread problems associated with drug resistance in many parasitic worms of livestock animals globally.