title: High-Resolution Genetics Identifies the Lipid Transfer Protein Sec14p as Target for Antifungal Ergolines.
abstract: Invasive infections by fungal pathogens cause more deaths than malaria worldwide. We found the ergoline compound NGx04 in an antifungal screen, with selectivity over mammalian cells. High-resolution chemogenomics identified the lipid transfer protein Sec14p as the target of NGx04 and compound-resistant mutations in Sec14p define compound-target interactions in the substrate binding pocket of the protein. Beyond its essential lipid transfer function in a variety of pathogenic fungi, Sec14p is also involved in secretion of virulence determinants essential for the pathogenicity of fungi such as Cryptococcus neoformans, making Sec14p an attractive antifungal target. Consistent with this dual function, we demonstrate that NGx04 inhibits the growth of two clinical isolates of C. neoformans and that NGx04-related compounds have equal and even higher potency against C. neoformans. Furthermore NGx04 analogues showed fungicidal activity against a fluconazole resistant C. neoformans strain. In summary, we present genetic evidence that NGx04 inhibits fungal Sec14p and initial data supporting NGx04 as a novel antifungal starting point.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Ireos
authors.identifier: http://orcid.org/0000-0002-2493-6183
authors.initials: I
authors.lastname: Filipuzzi
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Cotesta
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Perruccio
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Knapp
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
authors.forename: Yue
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Studer
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Verena
authors.initials: V
authors.lastname: Pries
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Riedl
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Helliwell
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Katarina T
authors.initials: KT
authors.lastname: Petrovic
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: N Rao
authors.initials: NR
authors.lastname: Movva
authors.affiliation: Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Sanglard
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
authors.forename: Jianshi
authors.initials: J
authors.lastname: Tao
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D004873:Ergolines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D002352:Carrier Proteins; D004873:Ergolines; C100642:SEC14L1 protein, human; C030363:lipid transfer protein