Conference Agenda

The treatment of malaria, an infectious disease caused by Plasmodium parasites, relies on numerous chemotherapies that are hampered by drug resistance. New antimalarial drugs with mechanisms of action different to currently used drugs are required to combat Plasmodium drug resistance. Robenidine is an antiparasitic drug with modest activity against P. falciparum (50% growth inhibitory concentration; IC₅₀ 0.76 µM) and unknown mode of action. To aid in the identification of new antimalarial drug candidates, a library of robenidine analogues was assessed for improved activity and selectivity for P. falciparum over mammalian cells. Multiple compounds with hit and early-lead activity and selectivity were identified, including NCL123 and NCL146, which demonstrated P. falciparum IC₅₀ values <0.1 µM and selectivity indices of >100. While in vivo studies with NCL123 and NCL146 demonstrated that further optimisation is needed to facilitate cures in mice infected with P. berghei ANKA, both compounds were well-tolerated and structural activity relationships have been useful in identifying avenues to improve this activity. Preliminary mode of action studies with NCL146 also suggest that this compound may have an unexploited mode of action associated with lipid biosynthesis, membrane function and cellular trafficking.

Proguanil is a used in combination with atovaquone to prevent and treat malaria. Activity of proguanil is thought to be due to its ability to potentiate atovaquone activity and the potent antiplasmodial activity of its in vivo metabolite, cycloguanil. Plasmodium falciparum resistance to cycloguanil is known to be due to mutations in the dihydrofolate reductase, but studies on proguanil resistance are lacking given it was essentially considered a prodrug. We overturned this dogma showing that proguanil has slow action activity against P. falciparum laboratory lines in vitro (Pf3D7 IC₅₀ 110 nM)¹. Here, we investigated thirteen culture-adapted P. falciparum isolates collected in eastern Uganda with low ex vivo sensitivity to proguanil². The in vitro sensitivity of the culture-adapted isolates to proguanil was assessed using 48 h, 72 h and 96 h growth-inhibition assays. While proguanil resistance was not confirmed in these studies, proguanil demonstrated slow-action activity against field isolates with 96 h IC₅₀ values of approximately 80-430 nM. These data extend our understanding of proguanil action to more clinically relevant field isolates, adding to findings that indicate that the antiplasmodial activity of the proguanil-atovaquone combination may be more complicated than previously thought.

Malaria remains a persistent global health threat leading to around 600,000 deaths annually. Resistance of Plasmodium parasites to most available drugs is significantly impacting prevention and control efforts. Combating resistance requires a clear understanding of drug mode of action, which remains incomplete for several current options. One such drug combination is atovaquone-proguanil. Atovaquone targets the cytochrome bc1 complex, and proguanil, originally developed as a prodrug, is converted in vivo to the dihydrofolate reductase (DHFR) inhibitor cycloguanil. While proguanil has been shown to potentiate the activity of atovaquone in vitro, for decades proguanil was thought to lack intrinsic activity. However, we showed that proguanil has a potent slow-acting in vitro antiplasmodial activity that is distinct from the folate metabolism pathway1. To try to identify the target/s of proguanil’s slow-action activity, we employed solvent-induced protein precipitation combined with mass spectrometry to assess protein stability in the presence of proguanil. Here, data will be presented on one of several candidate proteins stabilized by proguanil. Conditional knockdown is being performed in wildtype Plasmodium falciparum using TetR-DOZI and CRISPR-Cas9 Guide RNA constructs. Future work will include confirmation of knockdown and phenotypic assays with proguanil to assess changes in sensitivity to this drug.

The Australian sheep blowfly, Lucilia cuprina, is the principal cause of flystrike (cutaneous myiasis) in sheep, incurring losses of ~AU$320 million annually and inflicting severe welfare impacts in sheep. Current treatment includes insecticides and surgical mulesing; however, heavy reliance on insecticides has accelerated resistance, while mulesing draws strong public opposition due to animal welfare concerns—undermining both ethics and economic outcomes. Sustainable alternatives will be explored through the discovery and validation of novel blowfly-specific molecular targets identified using population genetic data from blowfly populations across Australia. RNA interference (RNAi) will be used to silence top molecular targets and protein modelling, and larval bioassays will be used for identifying and testing top candidate compounds. This project is expected to provide validated targets and candidate compounds for L. cuprina as the basis for novel larvicides to overcome existing insecticide resistance and reduce dependence on mulesing.

Gastrointestinal parasitic infections (GIP) are a major constraint to small ruminant production in Sri Lanka, yet a comprehensive synthesis of their epidemiology and anthelmintic resistance (AR) is lacking. This systematic review synthesised evidence on GIP, AR, and key knowledge gaps. A search of Web of Science, PubMed, Scopus, and CAB Abstracts (1971–January 2025), cross-checked with Google Scholar, identified 34 studies. Study quality was assessed using the Joanna Briggs Institute (JBI) prevalence checklist, and apparent prevalence was adjusted to true prevalence using the Rogan–Gladen estimator. In goats, prevalence ranged from 74–78%, while sheep showed seasonal prevalence of 84% (dry) and 92% (wet), with higher true prevalence after diagnostic adjustment. Predominant nematodes in goats were Haemonchus contortus (90%), Oesophagostomum columbianum (88%), Trichostrongylus colubriformis (76%), and Strongyloides spp. (72.5%). In sheep, Haemonchus contortus, Toxocara spp., and Trichuris spp. were common. AR was documented against benzimidazoles and levamisole, with Haemonchus spp. consistently implicated. Estimated economic losses in goats were LKR 230 million, based on limited data. Studies were heterogeneous in diagnostics, limiting comparability. These findings highlight critical gaps in parasite prevalence, species distribution, and AR, and underscore the need for coordinated, standardised national surveillance for sustainable parasite control in Sri Lanka.