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.
Highlights
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
The fifth class of anti-fungals are formed by the pyrimidine analogs like flucytosine that interfere with pyrimidine metabolism and RNA/DNA and protein synthesis[2,3,5,6,7,8]
Results indicate that M. pachydermatis enzymes homoserine dehydrogenase (MpHSD), MpHCS, MpSDH are targets to treat M. pachydermatis infections
Summary
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]. A frequently used approach is Gene Essentiality Analysis (GEA) that analysis the impact of in silico deletions to identify potentially essential genes for growth of an organism[12,14] This approach provides useful information about the metabolism of target organisms, which can be used to nominate therapeutic candidates[13,15,16]. Results indicate that MpHSD, MpHCS, MpSDH are targets to treat M. pachydermatis infections
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
