Biology subjects

Brunke, S.

Publications and source records attributed to Brunke, S..

6 recordsLinked to original sources

bioRxiv2026

The fungal transcription factor SmpR coordinates secondary metabolism and antibacterial defence in Aspergillus fumigatus during interspecies interaction

Aspergillus fumigatus, an opportunistic human fungal pathogen, encodes numerous secondary metabolite biosynthetic gene clusters (BGCs) that are tightly regulated and often remain silent under standard conditions. Co-cultivation with Streptomyces rapamycinicus or treatment with the secondary metabolite from this species, the arginoketide azalomycin F, induce the otherwise silent fumicycline (fcc) BGC of A. fumigatus. To elucidate the underlying regulatory circuitry, we performed transcriptome analyses of A. fumigatus exposed to azalomycin F or co-cultured with S. rapamycinicus. Both conditions triggered a coordinated antibacterial response, characterized by induction of specific secondary metabolites and antibacterial effectors, alongside repression of other BGCs, including those for fusarinine C, pyripyropene A, and fumagillin. Among the most strongly induced genes was a zinc cluster transcription factor, designated SmpR for secondary metabolite multiple pathway regulator, which is conserved within Ascomycota. SmpR expression was selectively induced by azalomycin F, specific Streptomyces species and other bacteria isolated from soil such as Kribbella spp. and Arthrobacter spp.. Functional analyses revealed that SmpR is required for activation of the fumicycline BGC: its deletion reduced, whereas its overexpression enhanced fumicycline production independently of external stimuli. We further demonstrate that SmpR acts upstream of the pathway-specific regulator FccR and additionally controls multiple antibacterial BGCs, including those for hexadehydroastechrome, helvolic acid and xanthocillin. Together, our data identify SmpR as a key regulator coordinating antibacterial secondary metabolism in response to bacterial signals in A. fumigatus.

microbiology↗

bioRxiv2024

Competitive fungal commensalism mitigates candidiasis pathology

The mycobiota are a critical part of the gut microbiome, but host-fungal interactions and specific functional contributions of commensal fungi to host fitness remain incompletely understood. Here we report the identification of a new fungal commensal, Kazachstania heterogenica var. weizmannii, isolated from murine intestines. K. weizmannii exposure prevented Candida albicans colonization and significantly reduced the commensal C. albicans burden in colonized animals. Following immunosuppression of C. albicans colonized mice, competitive fungal commensalism thereby mitigated fatal candidiasis. Metagenome analysis revealed K. weizmannii presence among human commensals. Our results reveal competitive fungal commensalism within the intestinal microbiota, independent of bacteria and immune responses, that could bear potential therapeutic value for the management of C. albicans-mediated diseases.

immunology↗

bioRxiv2023

A synthetic peptide mimic kills Candida albicans and synergistically prevents infection

More than two million people worldwide are affected by life-threatening, invasive fungal infections annually. Candida species are the most common cause of nosocomical, invasive fungal infections and are associated with mortality rates above 40%. Despite the increasing incidence of drug-resistance, the development of novel antifungal formulations has been limited. Here we investigate the antifungal mode of action and therapeutic potential of positively charged, synthetic peptide mimics to combat infections by Candida albicans. These synthetic polymers cause stress to the endoplasmic reticulum and affect protein glycosylation, a distinct mode of action compared to currently approved antifungal drugs. The most promising polymer composition caused damage to the mannan layer of the cell wall, with additional membrane-disrupting activity. The synergistic combination of the polymer with caspofungin prevented infection of human epithelial cells in vitro, improved fungal clearance by human macrophages, and significantly increased host survival in a Galleria mellonella model of systemic candidiasis. Additionally, prolonged exposure of C. albicans to the synergistic combination of polymer and caspofungin did not lead to the evolution of resistant strains in vitro. Together, this work highlights the enormous potential of these synthetic peptide mimics to be used as novel antifungal formulations as well as adjunctive antifungal therapy.

microbiology↗

bioRxiv2021

The landscape of toxic intermediates in the metabolic networks of pathogenic fungi reveals targets for antifungal drugs

The burden of fungal infections for humans, animals and plants is widely underestimated and comprises deadly infections as well as great economic costs. Despite that, antifungal drugs are scarce and emergence of resistance in fungal strains contributes to a high mortality. To overcome this shortage, we propose toxic intermediates and their controlling enzymes in metabolic pathways as a resource for new targets and provide a web-service, FunTox-Networks to explore the landscape of toxic intermediates in the metabolic networks of fungal pathogens. The toxicity of metabolites is predicted by a new random forest regression model and is available for over one hundred fungal species. Further, for major fungal pathogens, metabolic networks from the KEGG database were enriched with data of toxicity and regulatory effort for each enzyme to support identification of targets. We determined several toxic intermediates in fungal-specific pathways like amino acid synthesis, nitrogen and sulfur assimilation, and the glyoxylate bypass. For the latter, we show experimentally that growth of the pathogen Candida albicans is inhibited when the detoxifying enzymes Mls1 and Hbr2 are deleted and toxic glyoxylate accumulates in the cell. Thus, toxic pathway intermediates and their controlling enzymes represent an untapped resource of antifungal targets.

systems biology↗

bioRxiv2021

Transient mitochondria dysfunction confers fungal cross-resistance between macrophages and fluconazole

Loss or inactivation of antivirulence genes is an adaptive strategy in pathogen evolution. Candida glabrata is an important opportunistic pathogen related to bakers yeast, with the ability to both, quickly increase its intrinsic high level of azole resistance and persist within phagocytes. During C. glabratas evolution as a pathogen, the mitochondrial DNA polymerase, CgMip1, has been under positive selection. We show that CgMIP1 deletion not only triggers loss of mitochondrial function and a petite phenotype, but increases C. glabratas azole and ER stress resistance, and importantly, its survival in phagocytes. The same phenotype is induced by fluconazole and by exposure to macrophages, conferring a cross-resistance between antifungals and immune cells, and can be found in clinical isolates despite its slow growth. This suggests that petite constitutes a bet-hedging strategy of C. glabrata, and potentially a relevant cause of azole resistance. Mitochondrial function may therefore be considered a potential antivirulence factor.

evolutionary biology↗

bioRxiv2019

Phagocytic predation by the fungivorous amoeba Protostelium aurantium targets metal ion and redox homeostasis

Predatory interactions among microbes are considered to be a major evolutionary driving force for biodiversity and the defense against phagocytic killing. The fungivorous amoeba Protostelium aurantium has a wide fungal food spectrum but strongly discriminates among major pathogenic members of the Saccharomycotina. While C. albicans is not recognized, C. glabrata is rapidly internalized, but remains undigested. Phagocytic killing and feeding by P. aurantium is highly effective for the third major fungal pathogen, C. parapsilosis. Here we show that the different prey patterns of the three yeasts were reflected by distinct transcriptional responses, indicating fungal copper and redox homeostasis as primary targets during intracellular killing of C. parapsilosis. Gene deletions in this fungus for the highly expressed copper exporter Crp1 and the peroxiredoxin Prx1 confirmed their role in copper and redox homeostasis, respectively and identified methionine biosynthesis as a ROS sensitive metabolic target during predation. Both, intact Cu export and redox homeostasis contributed to the survival of C. parapsilosis not only when encountering P. aurantium, but also in the presence of human macrophages. As both genes were found to be widely conserved within the entire Candida clade, our results suggest that they could be part of a basic tool-kit to survive phagocytic attacks by environmental predators.

microbiology↗