Discovery research highlights

Established in February 2025, the WHO Discovery Research Working Group for Skin NTDs aims to strengthen the connection between basic research and WHO's implementation-focused skin NTD programme and policies. Sharing research highlights is one way to bring emerging evidence into discussions about disease understanding, treatment, prevention and research priorities. Contributions from members showcase progress in Buruli ulcer, cutaneous leishmaniasis and scabies, alongside a shared call to accelerate vaccine development.
Understanding and targeting tissue damage in Buruli ulcer
Research from Professor Rachel Simmonds FRSB, Head of Microbes, Infection & Immunity at the University of Surrey, Guildford, United Kingdom, and colleagues is revealing how mycolactone, the toxin produced by Mycobacterium ulcerans, damages host tissues. Hall and colleagues showed that mycolactone disrupts lysosome function by blocking Sec61, a gateway involved in protein processing in the endoplasmic reticulum. This prevents production of essential components of the V-ATPase proton pump, compromising the acidification needed for normal lysosomal function. The findings offer new insights into toxin-induced cell damage and raise questions about how these changes affect host defence. [1]
A complementary study by Hsieh and colleagues showed that mycolactone disrupts the protective sugar-rich layer on blood vessel cells, known as the glycocalyx, and the underlying basement membrane. These changes allow fibrinogen, a blood-clotting protein, to escape into surrounding tissue, providing a mechanism that may contribute to skin necrosis. Together, these studies identify processes worth investigating as targets for limiting tissue damage and disability. [2]
Dr Louisa Warryn, Postdoctoral Scientific Collaborator at the Swiss Tropical and Public Health Institute, Allschwil, Switzerland, and colleagues are pursuing complementary therapeutic approaches. Their analysis of two chemical scaffolds targeting the mycobacterial respiratory chain identified activity against M. ulcerans, expanding the chemical starting points for drug development beyond telacebec. [3] In separate work, Warryn and Paris combined bacterial viability testing with a mycolactone-detecting ELISA to screen the MMV Pandemic Response Box. This identified compounds that reduce toxin production without necessarily reducing bacterial viability, opening a route towards treatments that disarm bacterial virulence. These early findings support further assessment of both antibacterial and toxin-directed strategies for Buruli ulcer. [4]
Using human infection to guide vaccine discovery
Associate Professor Wim Adriaensen, Head of the Clinical Immunology Unit, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium, contributed two publications on leishmaniasis vaccine discovery. For cutaneous leishmaniasis, de Vrij and colleagues examined lesions from 27 Ethiopian patients using immunopeptidomics, which identifies the protein fragments presented to the immune system. They detected 580 previously undescribed Leishmania aethiopica epitopes derived from 398 antigens. Recurrent and conserved targets provide candidates for vaccine research, while the finding that prediction algorithms missed many naturally presented epitopes underscores the value of studying human infection directly. These promising antigen targets identified still require testing to determine whether they induce protective immunity. [5]
In an accompanying perspective, Adriaensen and colleagues propose an antigen-discovery framework combining immunopeptidomics, single-cell multiomics, T-cell receptor profiling and controlled human infection models. Their central message is that vaccine design needs stronger evidence about which parasite antigens are presented during early human infection. This provides a research agenda for prioritising vaccine candidates on biological evidence. [6]
Mrs Samantha Vermaak, Co-Investigator and Executive Manager of the VALIDATE Vaccine R&D Network, Centre for Clinical Vaccinology and Tropical Medicine, Jenner Institute, University of Oxford, United Kingdom, highlighted a broader perspective from Wang and colleagues. This paper, informed by the VALIDATE Network's May 2025 workshop in Bogotá, calls for coordinated action on vaccines for leishmaniasis, leprosy and Buruli ulcer. It advocates increased vaccine research funding, integration of NTD vaccine development into preparedness and response policies, and meaningful patient and public engagement. For the WHO Skin NTDs Team, these recommendations highlight opportunities to connect scientific advances with investment, partnerships and community priorities. [7]
Towards a simpler treatment for scabies
Dr Deepani Fernando and Professor Katja Fischer at the QIMR Berghofer Medical Research Institute, Brisbane, Australia and collaborating colleagues at Universities of Melbourne and Queensland are developing a topical combination scabicide of abametapir, the active ingredient of an approved head-lice treatment, and flavesone, a β-triketone derived from mānuka oil. An in vitro study demonstrated rapid killing of scabies mites and eggs [8]. A prior study showed that abametapir and mānuka oil inhibit common scabies-associated pathogens, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus dysgalactiae subsp. equisimilis, and Acinetobacter baumannii, [9] alongside scabicidal activity. A subsequent preclinical study, evaluating efficacy and pharmacokinetics in vivo in a porcine model for scabies, is underway.
These findings support further development of a potentially simpler treatment, but human efficacy and safety remain to be established. If confirmed clinically, activity against both mites and eggs could reduce the need for repeat applications and ease treatment delivery in resource-limited settings.
Across these contributions, discovery research is helping explain tissue injury, identify therapeutic targets and strengthen vaccine design. The Working Group can help translate these advances into clearly defined research priorities, connecting laboratory findings with the practical needs of affected communities and skin NTD programmes.
REFERENCES
1. Hall BS et al. A mycobacterial Sec61 inhibitor disrupts lysosome function by blocking Vacuolar-ATPase biosynthesis. European Journal of Cell Biology. 2026;105:151541. https://doi.org/10.1016/j.ejcb.2026.151541
2. Hsieh LTH et al. The Mycobacterium ulcerans toxin mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosis. eLife. 2025;12:RP86931. https://doi.org/10.7554/eLife.86931
3. Warryn L et al. The Mycobacterial cyt-bc1:aac3 Oxidase as a Drug Target: Activities of Arylvinylpiperazine Amides and Aminoquinazolines against Mycobacterium ulcerans. Journal of Medicinal Chemistry. 2026. https://doi.org/10.1021/acs.jmedchem.6c01076
4. Warryn L, Paris DH. Activity of MMV Pandemic Response Box compounds against Mycobacterium ulcerans viability and mycolactone production. Microbiology Spectrum. 2026:e03968-25. https://doi.org/10.1128/spectrum.03968-25
5. de Vrij N et al. Immunopeptidomics of cutaneous leishmaniasis patients reveals the natural antigenic landscape. Frontiers in Immunology. 2026. https://doi.org/10.3389/fimmu.2026.1765843
6. Adriaensen W et al. Breaking the deadlock in antigen discovery for Leishmania vaccines. Trends in Parasitology. 2026;42(3):183–191. https://doi.org/10.1016/j.pt.2026.01.005
7. Wang H et al. Accelerating vaccine research and development for skin neglected tropical diseases: A case for leishmaniasis, leprosy, and Buruli ulcer. PLOS Neglected Tropical Diseases. 2026;20(6):e0014375. https://doi.org/10.1371/journal.pntd.0014375
8. Fernando DD et al. In vitro assessment of a combination therapy of abametapir and flavesone as a novel topical single-dose scabies treatment. Journal of the American Academy of Dermatology. 2026. https://doi.org/10.1016/j.jaad.2026.01.019
9. Taylor S et al. Investigating the antibacterial properties of prospective scabicides. Biomedicines. 2022;10(12):3287. https://doi.org/10.3390/biomedicines10123287