Conference Agenda

Giardia duodenalis is a parasitic protist and the causative agent of giardiasis, a diarrhoeal disease that infects approximately one billion people annually and results in over 300 million cases of acute or chronic illness. Clinical presentations range from self-limiting disease to persistent and debilitating symptoms. Current treatment relies on a limited number of drugs from few chemical classes, many of which suffer from significant drawbacks, including prolonged treatment regimens, variable efficacy, severe side effects, and reduced effectiveness due to emerging drug resistance. To address these limitations, our team has developed a series of novel antiparasitic compounds, including lead candidates with substantially improved efficacy and selectivity compared with existing therapies.

While the mode of action of these compounds remains unclear, untargeted proteomic and drug‑combination studies suggest that they may act on the parasite cytoskeleton or phosphorylation‑based signalling machinery via previously unexplored mechanisms. These findings, along with ongoing efforts to define the mode of action of this compound series, will be discussed.

Malaria caused by Plasmodium falciparum remains a major global health challenge, with increasing resistance to frontline treatments highlighting an urgent need for new antimalarial therapies. The coenzyme A (CoA) biosynthesis pathway of P. falciparum represents a promising antimalarial drug target. Phosphopantothenoylcysteine synthetase (PPCS), the second enzyme in the pathway, is of particular interest due to its role as a flux-control step. To identify inhibitors of PfPPCS, we have screened ~50 compounds initially designed to inhibit the bacterial PPCS. RCS-33 and HDS-44 emerged as promising candidates, with antiplasmodial IC₅₀ values of ~1 µM. Although the activity of the compounds can be somewhat modulated by overexpression of PfPPCS, consistent with them being on target, their mechanism of action remains to be confirmed. We are currently generating RCS-33- and HDS-44-resistant parasites to try and identify the target via whole-genome sequencing of resistant parasites. We will also use an enzyme assay and purified PfPPCS to test directly whether the compounds are able to inhibit PfPPCS activity.

Malaria remains a leading cause of morbidity and mortality, with 608,000 deaths reported in 2022, predominantly among children under five in sub-Saharan Africa. The disease, predominantly caused by Plasmodium falciparum, faces escalating challenges due to the emergence of strains resistant to all frontline antimalarials, including artemisinins. This highlights an urgent need for new therapeutic strategies. While de novo drug discovery is slow and costly, repurposing existing compounds offers a rapid and cost-effective alternative.
We screened the Structural Genomics Consortium’s Donated Chemical Probes Library, which consists of compounds originally developed for human diseases, to identify candidates with antimalarial potential. From 200 compounds, 11 demonstrated sub-micromolar potency against the P. falciparum Pf3D7 reference strain and retained activity across five resistant lines. Their equipotent profiles suggest novel mechanisms of action distinct from existing drug classes. In vitro pulse activity assays further characterized compound speed-of-action and asexual stage-specific antimalarial activity.
Future work will employ unbiased multi-omics approaches, including as untargeted metabolomics, solvent proteome profiling and limited-proteolysis mass spectrometry, to elucidate molecular targets and validate these candidates as starting points for drug development. These findings highlight the potential of compound repurposing to accelerate antimalarial discovery and identify new druggable pathways to combat resistance.

The rapid emergence of drug‑resistant Plasmodium falciparum necessitates novel antimalarial strategies. Because parasite survival relies on extensive modification of host erythrocytes, host‑directed therapies represent an attractive approach. Here, we evaluated a panel of anticancer kinase inhibitors as potential antimalarials, initially hypothesising that they act through inhibition of host signalling pathways. We focused on the proposed requirement for activation of the human MAPK pathway in infected erythrocytes for parasite proliferation. The MAPK pathway tightly regulates cellular proliferation and survival, and its dysregulation in cancer has driven the development of numerous selective kinase inhibitors. Several compounds, displayed submicromolar potency against both asexual erythrocytic‑stage parasites and sexual gametocytes, indicating potential for dual curative and transmission‑blocking efficacy. However, detailed mechanistic studies of MEK1 inhibitors provided little evidence for host‑directed activity. Overexpression of human MEK1 in infected erythrocytes did not alter drug potency, parasites exposed continuously to one MEK1 inhibitor rapidly evolved resistance, and another inhibitor exhibited marked strain‑dependent activity across P. falciparum isolates. These observations support a parasite‑directed mode of action. Collectively, our findings demonstrate that human MEK1 is not essential for parasite proliferation. Despite host toxicity, parasite‑selective activity provides a platform for designing kinase inhibitor derivatives.

Gastrointestinal parasitism and inappropriate anthelmintic use are major constraints to goat production and key drivers of anthelmintic resistance (AR), particularly in low- and middle-income countries. This study evaluated parasite control practices recommended by veterinarians to goat farmers in Sri Lanka to identify critical gaps contributing to AR. An online questionnaire was distributed to 877 veterinarians following a pilot survey, and 122 completed responses (14%) were analysed. Data were collected on respondent demographics, knowledge of gastrointestinal helminths, diagnostic and control practices, anthelmintic use and AR awareness. Although respondents demonstrated sound knowledge (median confidence score: 70; mean: 65), diagnostic approaches relied on clinical signs (35%) and visual observation of worms in faeces (22%), with limited use of faecal egg counts (FEC). Limited diagnostic access (39%) and low farmer engagement (36%) were key barriers to recommending FEC. Albendazole, levamisole, and ivermectin were widely recommended; however, 41% of veterinarians estimated doses visually, increasing under-dosing risk. While 92% recognised AR as a major concern, 71% had never performed faecal egg count reduction tests. Multiple correspondence analysis identified distinct clusters of practices, separating experience-based from evidence-based approaches. These findings highlight critical gaps and the need for improved diagnostics, targeted training, farmer engagement, and national AR surveillance.