title: Hitting the caspofungin salvage pathway of human-pathogenic fungi with the novel lasso peptide humidimycin (MDN-0010).
abstract: Fungal infections have increased dramatically in the last 2 decades, and fighting infectious diseases requires innovative approaches such as the combination of two drugs acting on different targets or even targeting a salvage pathway of one of the drugs. The fungal cell wall biosynthesis is inhibited by the clinically used antifungal drug caspofungin. This antifungal activity has been found to be potentiated by humidimycin, a new natural product identified from the screening of a collection of 20,000 microbial extracts, which has no major effect when used alone. An analysis of transcriptomes and selected Aspergillus fumigatus mutants indicated that humidimycin affects the high osmolarity glycerol response pathway. By combining humidimycin and caspofungin, a strong increase in caspofungin efficacy was achieved, demonstrating that targeting different signaling pathways provides an excellent basis to develop novel anti-infective strategies.
authors.affiliation: Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany.
authors.forename: Vito
authors.initials: V
authors.lastname: Valiante
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain.
authors.forename: Maria Cândida
authors.initials: MC
authors.lastname: Monteiro
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Martín
authors.affiliation: Department of Systems Biology/Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Altwasser
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain.
authors.forename: Noureddine
authors.initials: N
authors.lastname: El Aouad
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: González
authors.affiliation: Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University Jena, Jena, Germany Integrated Research and Treatment Center, Center for Sepsis Control and Care Jena, University Hospital (CSCC), Jena, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Kniemeyer
authors.affiliation: Servicio de Micologia, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
authors.forename: Emilia
authors.initials: E
authors.lastname: Mellado
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Palomo
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: de Pedro
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Pérez-Victoria
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain.
authors.forename: José R
authors.initials: JR
authors.lastname: Tormo
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain axel.brakhage@hki-jena.de fernando.reyes@medinaandalucia.es olga.genilloud@medinaandalucia.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Reyes
authors.affiliation: Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Granada, Spain axel.brakhage@hki-jena.de fernando.reyes@medinaandalucia.es olga.genilloud@medinaandalucia.es.
authors.forename: Olga
authors.initials: O
authors.lastname: Genilloud
authors.affiliation: Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University Jena, Jena, Germany axel.brakhage@hki-jena.de fernando.reyes@medinaandalucia.es olga.genilloud@medinaandalucia.es.
authors.forename: Axel A
authors.initials: AA
authors.lastname: Brakhage
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000378:metabolism*; D000077336:Caspofungin; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D054714:Echinocandins / Q000494:pharmacology*; D006801:Humans; D055666:Lipopeptides; D010455:Peptides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010455:Peptides; D000077336:Caspofungin