New Therapeutic Candidates for the Treatment of Malassezia pachydermatis -Associated Infections

Abstract

the opportunistic pathogen Malassezia pachydermatis causes bloodstream infections in preterm infants or individuals with immunodeficiency disorders and has been associated with a broad spectrum of diseases in animals such as seborrheic dermatitis, external otitis and fungemia. The current approaches to treat these infections are failing as a consequence of their adverse effects, changes in susceptibility and antifungal resistance. Thus, the identification of novel therapeutic targets against M. pachydermatis infections are highly relevant. Here, Gene Essentiality Analysis and Flux Variability Analysis was applied to a previously reported M. pachydermatis metabolic network to identify enzymes that, when absent, negatively affect biomass production. Three novel therapeutic targets (i.e., homoserine dehydrogenase (MpHSD), homocitrate synthase (MpHCS) and saccharopine dehydrogenase (MpSDH)) were identified that are absent in humans. Notably, L-lysine was shown to be an inhibitor of the enzymatic activity of MpHCS and MpSDH at concentrations of 1 mM and 75 mM, respectively, while L-threonine (1 mM) inhibited MpHSD. Interestingly, L-lysine was also shown to inhibit M. pachydermatis growth during in vitro assays with reference strains and canine isolates, while it had a negligible cytotoxic activity on HEKa cells. Together, our findings form the bases for the development of novel treatments against M. pachydermatis infections. The yeast M. pachydermatis is part of the skin microbiota of domestic and wild animals and behaves as an opportunistic pathogen causing external otitis and seborrheic dermatitis in dogs and cats. Particular conditions such as the presence of lipid-rich microenvironments, a local imbalance of the natural microbiota and altered immune states favor these infections 1. Dermatologic infections caused by M. pachydermatis often exhibit a chronic (recurrent) course and their treatment can be complicated due to the ability of this yeast to form biofilms 1. In addition, M. pachydermatis causes bloodstream infections in preterm infants or in individuals with immunodeficiency disorders. These infections are related to contamination of medical devices such as catheters, the transmission through medical staff and the administration of lipids through intravenous way 2,3. Recently, several factors contributing to M. pachydermatis virulence have been determined, which include the production of proteinases, phospholipases, hyaluronidases, and chondroitin-sulfatases 4. Currently, five classes of antifungal agents are used orally, topically or intravenously for the treatment of fungal infections. The first class is formed by the azoles (ketoconazole, itraconazole, clotrimazole, miconazole, and

Urine Metabolomics Study on Potential Hepatoxic Biomarkers Identification in Rats Induced by Aurantio-Obtusin

“…It is formed by homocitrate synthase due to propionyl-CoA carboxylase deficiency. Homocitrate synthase is considered as a novel therapeutic target of immunologic deficiency syndromes ( Sastoque et al., 2020 ). This study speculated that aurantio-obtusin interfered with homocitric acid by affecting homocitrate synthase, but the relationship between aurantio-obtusin and immune deficiency needed further study.…”

Malassezia: Zoonotic Implications, Parallels and Differences in Colonization and Disease in Humans and Animals

“…With increased recognition of azole resistance in Malassezia species, there has also been an expansion in the investigation of alternative treatment approaches, including photodynamic therapy, natural products, antifungal peptides and proteinase inhibitors [ 443 , 454 , 455 , 456 , 457 , 458 , 459 ].…”

In vitro sensitivity of Malassezia furfur isolates from HIV-positive and negative patients to antifungal agents

“…The culture medium used was Sabouraud supplemented with 0,5% Tween 40 and 0,5% Tween 60. Previous studies used this medium and showed adequate growth and easy visual evaluation of the results 11 , 15 .…”

“…Lysine is one of these candidates showing yeast growth inhibition in vitro. However, further studies are required 11 . Other candidates include essential oils from different plants 12 .…”