New Therapeutic Candidates for the Treatment of Malassezia pachydermatis -Associated Infections.
Animals
Cell Line
Dermatomycoses
/ drug therapy
Dose-Response Relationship, Drug
Fungal Proteins
/ antagonists & inhibitors
Fungemia
/ drug therapy
Genes, Essential
Homoserine Dehydrogenase
/ antagonists & inhibitors
Humans
Lysine
/ pharmacology
Malassezia
/ drug effects
Oxo-Acid-Lyases
/ antagonists & inhibitors
Saccharopine Dehydrogenases
/ antagonists & inhibitors
Threonine
/ pharmacology
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
17 03 2020
17 03 2020
Historique:
received:
18
12
2019
accepted:
24
02
2020
entrez:
19
3
2020
pubmed:
19
3
2020
medline:
15
12
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32184419
doi: 10.1038/s41598-020-61729-1
pii: 10.1038/s41598-020-61729-1
pmc: PMC7078309
doi:
Substances chimiques
Fungal Proteins
0
Threonine
2ZD004190S
Homoserine Dehydrogenase
EC 1.1.1.3
Saccharopine Dehydrogenases
EC 1.5.1.-
homocitrate synthase
EC 2.3.3.14
Oxo-Acid-Lyases
EC 4.1.3.-
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4860Références
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