Christoph Müller

Christoph Müller
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Christoph verified their affiliation via an institutional email.
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Christoph verified their affiliation via an institutional email.
Ludwig-Maximilians-Universität in Munich | LMU · Department of Pharmacy

Dr. rer. nat.

About

99
Publications
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1,238
Citations

Publications

Publications (99)
Article
In this study, an advanced nanofiber breast cancer in vitro model was developed and systematically characterized including physico-chemical, cell-biological and biophysical parameters. Using electrospinning, the architecture of tumor-associated collagen signatures (TACS5 and TACS6) was mimicked. By employing a rotating cylinder or static plate coll...
Article
Full-text available
Aspergillus fumigatus is intrinsically resistant to the widely used antifungal fluconazole, and therapeutic failure can result from acquired resistance to voriconazole, the primary treatment for invasive aspergillosis. The molecular basis of substrate specificity and innate and acquired resistance of A. fumigatus to azole drugs were addressed using...
Article
Full-text available
Dispersive solid-phase extraction (dSPE) is a crucial step for multiresidue analysis used to remove matrix components from extracts. This purification prevents contamination of instrumental equipment and improves method selectivity, sensitivity, and reproducibility. Therefore, a clean-up step is recommended, but an over-purified extract can lead to...
Article
Full-text available
Azole antifungals inhibit the sterol C14-demethylase (CYP51/Erg11) of the ergosterol biosynthesis pathway. Here we show that the azole-induced synthesis of fungicidal cell wall carbohydrate patches in the pathogenic mold Aspergillus fumigatus strictly correlates with the accumulation of the CYP51 substrate eburicol. A lack of other essential ergost...
Preprint
Full-text available
The pronounced skin tropism and pan-antifungal resistance traits of the fungal pathogen Candida auris stand out as a serious health threat. Here, we show that a carbonic sensing pathway (CSP) promotes development of resistance to amphotericin B through a reactive oxygen species (ROS) response, as well as ectopic cell wall and membrane lipid homeost...
Article
Full-text available
Bats are the second largest mammalian order and are an endangered species group with a strong need for contamination monitoring. To facilitate non-invasive monitoring of the ecological burden in bat populations, a multiresidue method for the simultaneous quantification of 119 analytes including pesticides, persistent organic pollutants (POPs), acti...
Article
The liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol, a final intermediate in cholesterol biosynthesis, has been identified as a selective LXR ligand that suppresses inflammation without inducing lipogenesi...
Preprint
Azole antifungals inhibit the sterol C14-demethylase (CYP51/Erg11), a key enzyme in the ergosterol biosynthesis pathway. They have fungistatic effects against yeasts but fungicidal effects against molds. The molecular basis for this difference remained unknown. The sequence of enzymatic steps required for ergosterol biosynthesis is different in yea...
Article
Full-text available
Azole antifungals remain the “gold standard” therapy for invasive aspergillosis. The world-wide emergence of isolates resistant to this drug class, however, developed into a steadily increasing threat to human health over the past years. In Aspergillus fumigatus , major mechanisms of resistance involve increased expression of cyp51A encoding one of...
Article
Full-text available
The ergosterol pathway is a promising target for the development of new antifungals since its enzymes are essential for fungal cell growth. Appropriate screening assays are therefore needed that allow the identification of potential inhibitors. We developed a whole-cell screening method, which can be used to identify compounds interacting with the...
Article
Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects...
Article
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Background: Growing up on traditional European, and U.S. Amish, dairy farms, in close contact with cows and hay, protects children against asthma, and airway administration of extracts from dust collected from cowsheds of those farms prevents allergic asthma in mice. Objectives: This study sought to begin identifying farm-derived asthma-protecti...
Article
Full-text available
Invasive aspergillosis remains one of the most devastating fungal diseases and is predominantly linked to infections caused by the opportunistic human mold pathogen Aspergillus fumigatus. Major treatment regimens for the disease comprise the administration of antifungals belonging to the azole, polyene and echinocandin drug class. The prodrug 5-flu...
Article
Full-text available
The Annonaceae are an old family of flowering plants belonging to the order Magnoliales, distributed mainly in tropical regions. Numerous Annonaceae species find ethnobotanical use for curing a broad range of diseases, among them cancer and infections by diverse pathogens. Hence, bioactive natural products from Annonaceae have received considerable...
Article
Full-text available
A major limitation of current reports on insect declines is the lack of standardized, long-term, and taxonomically broad time series. Here, we demonstrate the utility of environmental DNA from archived leaf material to characterize plant-associated arthropod communities. We base our work on several multi-decadal leaf time series from tree canopies...
Article
Protein particle formation during peristaltic pumping of biopharmaceuticals is due to protein film formation on the inner tubing surface followed by rupture of the film by the roller movement. Protein adsorption can be prevented by addition of surfactants as well as by increasing the hydrophilicity of the inner surface. Attempts based on covalent s...
Preprint
Invasive aspergillosis remains one of the most devastating fungal diseases and is predominantly linked to infections caused by the opportunistic human mold pathogen Aspergillus fumigatus. Major treatment regimens for the disease comprise the administration of antifungals belonging to the azole, polyene and echinocandin drug class. The prodrug 5-flu...
Article
Bats are strictly protected throughout Europe. They are a highly diverse order of mammals in terms of body size, body weight, migratory behaviour, trophic niche specialisation and habitat use. The latter ranges from urban areas and arable land to forest. Due to their low reproductive rate, environmental stressors can have a major impact on bat popu...
Preprint
Full-text available
A major limitation of current reports on insect declines is the lack of standardized, long-term, and taxonomically broad time series. Here, we demonstrate the utility of environmental DNA from archived leaf material to characterize plant-associated arthropod communities. We base our work on several multi-decadal leaf time series from tree canopies...
Article
Full-text available
Persistent organic pollutants, pesticides and biocides have a harmful impact on biological diversity. Besides short-term toxic effects on directly exposed organisms, they can have long-term effects resulting in changes of habitats and food chains. Their widespread use makes contact with pesticides and their residues inevitable for some wildlife. Ho...
Article
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The aliphatic heterocycles piperidine and morpholine are core structures of well-known antifungals such as fenpropidin and fenpropimorph, commonly used as agrofungicides, and the related morpholine amorolfine is approved for the treatment of dermal mycoses in humans. Inspired by these lead structures, we describe here the synthesis and biological e...
Article
During the last decade, the understanding of the biological functions of cholesterol biosynthesis intermediates has changed significantly. Particularly, the enzyme sterol dehydrocholesterol reductase 24 (DHCR24) has taken center stage as a potential drug target. Inhibition of DHCR24 leads to accumulation of the endogenous, biologically active metab...
Article
Full-text available
Significance Biosynthesis of sterols requires oxygen. This study identifies a previously unknown evolutionary adaptation in a eukaryote, which enables anaerobic growth in absence of exogenous sterols. A squalene–hopene cyclase, proposed to have been acquired by horizontal gene transfer from an acetic acid bacterium, is implicated in a unique abilit...
Article
In order to gain a better insight into pesticide and pollutant exposure of small (non-target) wildlife animals, a QuEChERS sample preparation method was first developed for 5 g liver tissues (e.g. hedgehog samples) and then downscaled for the analysis of 100 mg liver tissues (e.g. bat samples). The optimized (micro) QuEChERS methods used 1% acetic...
Preprint
Full-text available
Biosynthesis of sterols, which are key constituents of canonical eukaryotic membranes, requires molecular oxygen. Anaerobic protists and deep-branching anaerobic fungi are the only eukaryotes in which a mechanism for sterol-independent growth has been elucidated. In these organisms, tetrahymanol, formed through oxygen-independent cyclization of squ...
Article
Steroids play an important role in cell regulation and homeostasis. Many diseases like Alzheimer’s disease or Smith-Lemli-Opitz syndrome are known to be associated with deviations in the steroid profile. Most published methods only allow the analysis of small subgroups of steroids and cannot give an overview of the total steroid profile. We develop...
Article
In order to gain a better insight into pesticide and pollutant exposure in forests, a rapid and sensitive gas chromatorgraphy- tandem mass spectrometry (GC-MS/MS) method for the determination of 208 pesticide residues in leaves and needles has been established. The modified QuEChERS (quick, easy, cheap, effective, rugged and safe) approach uses 2 g...
Article
DMSO is widely used as powerful cryoprotectant for the storage and transport of frozen cells. Beyond this established application of DMSO, we could now show that it has also promising lyoprotectant effects in the field of lyophilisation of therapeutic cells. Freeze-drying of HaCaT keratinocytes in 10% HES, 5% HE and in presence of DMSO led to an in...
Article
The role of two-pore channel 2 (TPC2), one of the few cation channels localized on endolysosomal membranes, in cancer remains poorly understood. Here, we report that TPC2 knockout reduces proliferation of cancer cells in vitro, affects their energy metabolism, and successfully abrogates tumor growth in vivo. Concurrently, we have developed simplifi...
Article
Full-text available
In a project aimed at the further development of the potent steroidal anti‐inflammatory Δ²⁴‐dehydrocholesterol reductase (DHCR24) inhibitor SH‐42 we worked out routes to ring B seco‐steroidal analogues. The required building blocks, bearing rings C and D of the parent steroidal structure, were synthesised starting from ergocalciferol. The novel sec...
Patent
The present invention relates to a method of preparing a barn dust extract, said barn dust extract, and a composition comprising said barn dust extract. The barn dust extract is useful in the prevention or treatment of a disease.
Article
Full-text available
Objectives: In this study, the pharmacological properties of six spirocyclic piperidines 1-6 showing very high σ1 receptor affinity (Ki = 0.2-16 nm) were investigated. Methods: In vitro receptor binding studies, retinal ganglion assay and in vivo capsaicin assay were used to determine the affinity, selectivity and activity. Influence on human tu...
Article
Significance Lipid metabolism is crucial to many (patho-)physiological processes, including inflammation. In particular, cholesterol biosynthesis has emerged as an exciting novel therapeutic target in numerous recent studies. Much is known about the early steps in cholesterol biosynthesis; however, the later steps have hitherto largely been neglect...
Article
Full-text available
In fungi, ergosterol is an essential component of the plasma membrane. Its biosynthesis from acetyl-CoA is the primary target of the most commonly used antifungal drugs. Here, we show that the pantothenate kinase Cab1p, which catalyzes the first step in the metabolism of pantothenic acid for CoA biosynthesis in budding yeast (Saccharomyces cerevisi...
Article
Distal cholesterol biosynthesis (CB) has recently taken center stage as a promising drug target in several diseases previously not linked to this biochemical pathway, including cardiovascular disease, cancer, multiple sclerosis and Alzheimer’s disease. Most enzymes involved in this pathway are hard to isolate, warranting dedicated analytical tools...
Article
Full-text available
Sulfoconjugates of sterols play important roles as neurosteroids, neurotransmitters, and ion channel ligands in health and disease. In most cases, sterol conjugate analysis is performed with liquid chromatography-mass spectrometry. This is a valuable tool for routine analytics with the advantage of direct sterol sulfates analysis without previous c...
Article
According to the European Pharmacopeia and the United States Pharmacopoeia dimethyl sulfoxide (DMSO) is a class 3 solvent and it is used in pharmaceutical industry amongst others as an additive for the lyophilisation process. DMSO has a very low vapour pressure and is therefore difficult to remove during freeze drying, with the result, that a signi...
Article
Full-text available
Mucorales are fungi with increasing importance in the clinics. Infections take a rapidly progressive course resulting in high mortality rates. The ergosterol biosynthesis pathway and sterol composition are of interest, since they are targeted by currently applied antifungal drugs. Nevertheless, Mucorales often exhibit resistance to these drugs, res...
Article
Full-text available
Cytochrome P450 enzymes (P450) play essential roles in redox metabolism in all domains of life including detoxification reactions and sterol biosynthesis. The activity of P450s is fuelled by two electron-transferring mechanisms, heme-independent P450 reductase (CPR) and the heme-dependent cytochrome b5 (CYB5)/cytochrome b5 reductase (CB5R) system....
Article
Full-text available
Candida albicans is an inhabitant of mucosal surfaces in healthy individuals but also the most common cause of fungal nosocomial blood stream infections, associated with high morbidity and mortality. As such life-threatening infections often disseminate from superficial mucosal infections we aimed to study the use of probiotic Lactobacillus rhamnos...
Data
Generation of three-dimensional mucosal models. Summary of the different media used to generate three dimensional models of human oral mucosa. (DOC)
Data
Glucose content in KGM-Gold™ medium after 18 h in presence or absence of keratinocytes. The upper panel shows the amount of glucose in the supernatants of differentially treated monolayers of TR146 keratinocytes. In some cases the medium was supplemented with glucose (5 mg/ml). The lower panel shows the amount of glucose in KGM-Gold™ medium incubat...
Data
Three-dimensional mucosal model. Reconstructed human oral epithelium (RHOE) at day 8 of cultivation. (A) Semi-thin section stained with toluidine blue and visualized by light microscopy at a 400-fold magnification. (B) Ultra-thin sections were contrasted with osmium and visualized by transmission electron microscopy. Arrows indicate desmosomes. Sca...
Data
pH in the supernatant of differentially treated oral keratinocytes. (DOC)
Data
Differences between KGM-Gold™ medium and MRS medium. LGG (1.9 x 106 CFU/ml) and C. albicans (1 x 106 CFU/ml) were inoculated to KGM-Gold™ or MRS broth. OD600 was determined immediately and after 12 h incubation. pH was determined after 12 h incubation. To assess hyphal growth C. albicans was allowed to grow for 18 h. (DOC)
Data
Results of gene expression analysis in Candida albicans cultivated in epithelial cells in presence and absence of Lactobacillus rhamnosus GG. (A) Quantification of gene expression in C. albicans 2 h and 6 h post-infection. (B) Gene expression in C. albicans after 2 h of infection. (C) Gene expression in C. albicans after 6 h of infection. (XLS)
Article
Starting from enantiomerically pure amino acids, 1,4-diazepanes with various substituents in 1, 2, and 4-position were synthesized following the late stage diversification strategy. The key step in the formation of the seven-membered ring was the intramolecular EDC coupling of amino acids 15, 26, and 39. The configuration in 2-position does not inf...
Article
Cinnamon is a traditional herbal drug, but more importantly, it is used as a flavor compound in the production of foodstuff. Due to the content of significant concentrations of coumarin in Cassia cinnamon, effective control of the coumarin content in seasonal bakery products like ginger bread and cinnamon biscuits is urgently needed. Here we presen...
Article
Fungal infections and their increasing resistance to antibiotics are an emerging threat to public health. Novel antifungal drugs, as well technologies that can help us bolster the antimicrobial pipeline and understand resistance mechanisms, are needed. The ergosterol biosynthetic pathway is one potential target for antifungal drugs. Here we describ...
Article
Full-text available
A miniaturized QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Save) approach combined with gas chromatography–tandem mass spectrometry (GC–MS/MS) has been developed for the simultaneous determination of nine pesticides (Cyflufenamide, Difenoconazole, Dimethomorph, Fluopicolide, Fluopyram, Metrafenone, Myclobutanil, Quinoxyfen, and Tebuconazol...
Article
Combination products have become popular formats for the delivery of parenteral medications. Bake-on siliconization of glass syringes or cartridges allows good piston break-loose and gliding during injection at low silicone levels. Although widely implemented in industry, still little is known and published on the effect of the bake-on process on t...
Article
Full-text available
Azole drugs selectively target fungal sterol biosynthesis and are critical to our antifungal therapeutic arsenal. However, resistance to this class of drugs, particularly in the major human mould pathogen Aspergillus fumigatus, is emerging and reaching levels that have prompted some to suggest that there is a realistic probability that they will be...
Data
Effects of hapC deletion on fungal load in organs of immunosuppressed mice. (A) Cortisone acetate immunosuppressed OF-1 mice challenged intranasally with 1x105 CFU/animal of A. fumigatus. Horizontal bars represent the median. aP < 0.05 vs. wt, bP < 0.05 vs. hapCREC; (B) Cyclophosphamide immunosuppressed OF-1 mice challenged intravenously with 3x104...
Data
Characterisation of purified recombinant proteins used in this study. (A) SDS-PAGE analysis of wt (HapB/HapC/HapE) and mutated CBC (HapB/HapC/HapEP88L) as well as recombinant HapX(24–158) protein. (B) Analysis of the solution heterotrimeric state of HapB/C/E and HapB/C/EP88L complexes by analytical size exclusion chromatography coupled light scatte...
Data
ChIP-Seq Peaks from genes coding for enzymes of the ergosterol biosynthetic pathway. Cultures were grown for 18 h in AMM at 37°C. TSS, putative transcriptional start site. (DOCX)
Data
Alignment of the native (-293) and repeat region (-327TR) of the cyp51A promoter bound by the CBC with the A. nidulans cycA region whose structure was elucidated in complex with the AnCBC. Yellow highlights indicate bases conserved in all three binding sites, blue in two of the three. Underlined bases identify those outside the core domain shown to...
Data
Scheme of site-directed integration of plasmids for cyp51A promoter mutations and gfp-tagged hapC. (A) cyp51A based plasmids were linearised using BsrGI and transformed into Δcyp51A. The same transformation procedure was carried out for all plasmids containing modified cyp51A promoter versions. (B) Site-directed integration of a plasmid harboring C...
Data
Oligonucleotides used in this study (5´→3´). (DOCX)
Article
Full-text available
Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. More...
Article
The cyclization of oxidosqualene to lanosterol, catalyzed by the enzyme oxidosqualene cyclase (OSC), goes through a number of carbocationic high energy intermediates (HEI), and mimicking these intermediates is a promising approach for the development of OSC inhibitors. 3-Arylpiperidines (or tetrahydropyridines) were designed as steroidomimetic ring...
Article
Full-text available
Fungal infections are a leading cause of morbidity and mortality for hospitalized patients, mainly because they remain difficult to diagnose and treat. Disease ranges from widespread superficial infections like vulvovaginal infections to life-threatening systemic candidiasis. For systemic mycoses only a restricted arsenal of antifungals is availabl...
Article
Recent studies have highlighted the role of impaired barrier function and aberrant epithelial cell responses in the pathogenesis of allergy and asthma. Epidemiological studies showed that children growing up on farms have a lower incidence of childhood asthma, which was attributed to high microbial exposure. Interestingly, microbial exposure was fo...
Article
Inhibition of concise enzymes in ergosterol biosynthesis is one of the most prominent strategies for anti-fungal chemotherapy. Nevertheless, the enzymes sterol C5-desaturase and sterol C22-desaturase, which introduce double bonds into the sterol core and side chain, have not been fully investigated yet for their potential as antifungal drug targets...
Article
Inhibition of concise enzymes in ergosterol biosynthesis is one of the most prominent strategies for antifungal chemotherapy. Nevertheless, the enzymes sterol C5-desaturase and sterol C22-desaturase, which introduce double bonds into the sterol core and side chain, have not been fully investigated yet for their potential as antifungal drug targets....
Article
A method for the determination of phytosterols in herbal medicinal products for the treatment of lower urinary tract symptoms and food products is described here. Using a convenient sample preparation protocol and sensitive gas chromatography ion trap mass spectrometry analysis, ten different sterols, among them five Δ(7)-phytosterols as typical co...