Abstract
New antimycotic drugs are challenging to find, as potential target proteins may have close human orthologs. We here focus on identifying metabolic targets that are critical for fungal growth and have minimal similarity to targets among human proteins. We compare and combine here: (I) direct metabolic network modeling using elementary mode analysis and flux estimates approximations using expression data, (II) targeting metabolic genes by transcriptome analysis of condition-specific highly expressed enzymes, and (III) analysis of enzyme structure, enzyme interconnectedness (“hubs”), and identification of pathogen-specific enzymes using orthology relations. We have identified 64 targets including metabolic enzymes involved in vitamin synthesis, lipid, and amino acid biosynthesis including 18 targets validated from the literature, two validated and five currently examined in own genetic experiments, and 38 further promising novel target proteins which are non-orthologous to human proteins, involved in metabolism and are highly ranked drug targets from these pipelines.
Highlights
The treatment of invasive fungal infections caused by the versatile saprophytic fungus Aspergillus fumigatus is challenging (Denning, 1998)
We have identified 64 targets including metabolic enzymes involved in vitamin synthesis, lipid, and amino acid biosynthesis including 18 targets validated from the literature, two validated and five currently examined in own genetic experiments, and 38 further promising novel target proteins which are non-orthologous to human proteins, involved in metabolism and are highly ranked drug targets from these pipelines
We combine three different bioinformatics approaches that we have previously developed to target the pathogen’s primary metabolism: (I) metabolic modeling: direct metabolic network modeling using elementary mode analysis and flux estimates constrained by applying gene expression data, (II) enzyme regulation-based strategy: targeting metabolic genes by transcriptome analysis of conditionspecific highly expressed enzymes, (III) protein-protein interaction-based strategy: analysis of enzyme structure, enzyme interconnectedness (“hubs”) and identification of pathogenspecific enzymes using orthology relations
Summary
The treatment of invasive fungal infections caused by the versatile saprophytic fungus Aspergillus fumigatus is challenging (Denning, 1998). While the healthy human immune system is able to fend off A. fumigatus infections in general, immune-deficient patients are highly vulnerable against invasive aspergillosis. Aspergillosis is one of the major lethal conditions in immunocompromised patients (Dagenais and Keller, 2009). Most potential protein targets for antimycotic development bear a considerable risk of toxic side effects for the patient as a similar protein might be present in the human host. Several anti-mycotic strategies exist, they are only partially effective due to the significant immunosuppression of those patients. The development of new therapeutic strategies against A. fumigatus infection is crucial
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