Etablierung von Ko-Kultivierungstechniken zur Anwendung in miniaturisierten Testsystemen für antibiotische Aktivität.

Master Thesis of Isabel Stalter, Hochschule Albstadt-Sigmaringen, performed in my lab in CPC-NPU: Establishment of co-cultivation techniques of antibiotics-producing actinomycetes and bacterial test strains as a screening tool for the detection of new antibiotics. The method was designed and optimized for a later potential use in a micro-fluidic test system. No Novartis-proprietary strains and no Novartis compounds were used in this work. The thesis is solely exploratory and does not refer to any Novartis-internal project

Optimierung von Kulturbedingungen zur mikrobiellen Herstellung von Ascomycin Derivaten.

Project work (thesis) of a student for the University of Dresden: Lab-scale optimization of medium composition and cultivation conditions for the fermentation of mutants for the microbial production of derivatives of Ascomycin. Scale-up to the pilot scale. All microbial strains are blinded, e.g. "mutant A". All compounds, although already published, are blinded, e.g. derivative A"

Die Auswahl der Torecke beim Elfmeter: Der Einfluss bewusster und unbewusster Hinweise auf Fußball-Experten und Fußball-Novizen

Weigelt M, Steingräber S, Schack T, Memmert D. Die Auswahl der Torecke beim Elfmeter: Der Einfluss bewusster und unbewusster Hinweise auf Fußball-Experten und Fußball-Novizen. In: Eder AB, Rothermund K, Schweinberger SR, Steffens MC, Wiese H, eds. 51. Tagung experimentell arbeitender Psycholog/Innen. Tagungsprogramm und Abstracts, 29. März - 1. April 2009 in Jena. Lengerich: Pabst; 2009: 38

4-Aminothiazolyl Analogs of GE2270 A: Antibacterial Lead Finding

4-Aminothiazolyl analogs of the antibacterial natural product GE2270 A (1) were designed, synthesized, and evaluated for G+ bacteria growth inhibition. The aminothiazole-based chemical template was evaluated for chemical stability and its decomposition revealed a novel, structurally simplified, des-thiazole analog of GE2270 A. Subsequent stabilization of the 4-aminothiazolyl functional motif was achieved and initial structure activity relationships defined

Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol

Biosynthesis of glycosylphosphatidylinositol (GPI) is required for anchoring proteins to the plasma membrane, and is essential for the integrity of the fungal cell wall. Here, we use a reporter gene-based screen in Saccharomyces cerevisiae for the discovery of antifungal inhibitors of GPI-anchoring of proteins, and identify the oligocyclopropyl-containing natural product jawsamycin (FR-900848) as a potent hit. The compound targets the catalytic subunit Spt14 (also referred to as Gpi3) of the fungal UDP-glycosyltransferase, the first step in GPI biosynthesis, with good selectivity over the human functional homolog PIG-A. Jawsamycin displays antifungal activity in vitro against several pathogenic fungi including Mucorales, and in vivo in a mouse model of invasive pulmonary mucormycosis due to Rhyzopus delemar infection. Our results provide a starting point for the development of Spt14 inhibitors for treatment of invasive fungal infections

Author Correction: Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol.

Biosynthesis of glycosylphosphatidylinositol (GPI) is required for anchoring proteins to the plasma membrane, and is essential for the integrity of the fungal cell wall. Here, we use a reporter gene-based screen in Saccharomyces cerevisiae for the discovery of antifungal inhibitors of GPI-anchoring of proteins, and identify the oligocyclopropyl-containing natural product jawsamycin (FR-900848) as a potent hit. The compound targets the catalytic subunit Spt14 (also referred to as Gpi3) of the fungal UDP-glycosyltransferase, the first step in GPI biosynthesis, with good selectivity over the human functional homolog PIG-A. Jawsamycin displays antifungal activity in vitro against several pathogenic fungi including Mucorales, and in vivo in a mouse model of invasive pulmonary mucormycosis due to Rhyzopus delemar infection. Our results provide a starting point for the development of Spt14 inhibitors for treatment of invasive fungal infections

FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p

FR171456 is a natural product with cholesterol-lowering properties in animal models, but its molecular target is unknown, which hinders further drug development. Here we show that FR171456 specifically targets the sterol-4-alpha-carboxylate-3-dehydrogenase (Saccharomyces cerevisiae—Erg26p, Homo sapiens—NSDHL (NAD(P) dependent steroid dehydrogenase-like)), an essential enzyme in the ergosterol/cholesterol biosynthesis pathway. FR171456 significantly alters the levels of cholesterol pathway intermediates in human and yeast cells. Genome-wide yeast haploinsufficiency profiling experiments highlight the erg26/ERG26 strain, and multiple mutations in ERG26 confer resistance to FR171456 in growth and enzyme assays. Some of these ERG26 mutations likely alter Erg26 binding to FR171456, based on a model of Erg26. Finally, we show that FR171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. The discovery of the target and binding site of FR171456 within the target will aid further development of this compound