Welcome to the IUMS 2022 Interactive Program

Abstract Body

Scabies is caused by infection with the ectoparasite Sarcoptes scabiei var. hominis. Scabies occurs worldwide but an especially high burden of disease is found in low and middle income countries and in some settings the community prevalence of scabies may be as high as 20-30%. In response to the high burden of disease, individual country commitments to control the disease and the emerging evidence that ivermectin-based mass drug administration (MDA) represents an effective control strategy scabies was added to the World Health Organization (WHO) list of Neglected Tropical Diseases (NTDs) in 2017.

In this talk I will cover key research and programmatic progess towards the control of scabies over the last decade and outline priorities for the coming decade.

Background and Aims

Malassezia forms the dominant eukaryotic microbial community on the human skin. The Malassezia genus possesses a repertoire of secretory hydrolytic enzymes involved in protein and lipid metabolism which alter the external cutaneous environment. The exact role of most Malassezia secreted enzymes, including those in interaction with the epithelial interface, are not well characterized.

Methods

In this study, we compared the expression level of secreted proteases, lipases, phospholipases, and sphingomyelinases of Malassezia globosa in healthy subjects and seborrheic dermatitis or atopic dermatitis patients. We observed upregulated gene expression of the previously characterized secretory aspartyl protease MgSAP1 in both the lesional and non-lesional skin sites of affected compared to healthy subjects. To explore the functional role of MgSAP1 in skin disease, we generated a knockout mutant of the homologous protease MfSAP1 in the genetically tractable Malassezia furfur.

Results

We observed the loss of MfSAP1 resulted in dramatic changes in cell adhesion and dispersal in both culture and a human 3D reconstituted epidermis model. In a murine model of Malassezia colonization, we further demonstrated that MfSAP1 contributes to inflammation as indicated by the reduced edema formation and myeloid cell infiltration with the knockout mutant versus wildtype M. furfur.

Conclusions

Taken together, we show that the secretory Malassezia aspartyl protease MfSAP1 has an important role in enabling a planktonic cellular state that can potentially aid in host colonization and additionally act as a virulence factor in barrier-compromised skin, further highlighting the importance of the contextual relevance when evaluating the functions of secreted microbial enzymes.

Background and Aims

Mycetoma is a Neglected Tropical Disease characterized by large subcutaneous swellings and the formation of grains. Mycetoma is treated with itraconazole and surgery with low success rates, resulting in amputations and social sigma. To improve the therapeutic success rates a novel drug is needed. Due to the lack of interest of pharmaceutical industry, the open source drug discovery program mycetOS was established.

Methods

In total 1360 compounds were screened for in vitro activity against M. mycetomatis. Compounds able to inhibit growth at 100 µM, 25 µM, and had an IC50 < 8 µM were selected for studying in vivo efficacy in our M. mycetomatis grain model in the invertebrate Galleria mellonella.

Results

In total 302 compounds were able to inhibit growth at 100 µM and 23 of those met all criteria to be screened in vivo. Of these 23, nine did prolong larval survival. These included 3 out of 7 azoles tested, olorofim, fenbendazole, MMV006357, MMV022478, MMV675968 and MMV1782387. Based on these results, 6 compound series were selected for further studying: fenarimols; aminothiazoles; phenotiazines; dihydrofolate reductase inhibitors; benzimidazoles and ketoximines. For the fenarimols in total 185 additional compounds were screened. By analyzing the in vitro activity and in vivo efficacy in relation to the chemical properties of the fenarimol it appears that the LogD value of a compound was important for in vivo efficacy.

Conclusions

Here we demonstrated that an open source drug discovery project such as MycetOS can be an effective way to identify novel lead compounds for fungal skinNTDs.