Hans Knöll Institute

Candida albicans is a leading cause of invasive candidiasis, a life-threatening infection with high mortality despite antifungal therapy. Echinocandins are first-line agents due to their fungicidal activity and low toxicity profile. Beyond direct killing, they may also modulate host immunity, e.g. through fungal cell wall remodeling. However, the systemic impact of echinocandins on human immune cells remains incompletely understood, particularly in the context of drug resistance. Using an ex vivo human whole-blood infection model, we assessed the effects of caspofungin during infection with echinocandin-susceptible (ECHS/FKSwt) and echinocandin-resistant (ECHR/FKSmut) C. albicans strains. Infection alone triggered a strong and conserved transcriptional immune program enriched for innate recognition and inflammatory pathways. Caspofungin treatment during infection with the susceptible strain selectively amplified these responses, engaging a sequential cascade of host defenses that linked pathogen recognition with innate effector functions and adaptive polarisation. In contrast, caspofungin induced only minimal transcriptional changes in resistant strain infections or in uninfected blood. These findings demonstrate that caspofungin efficacy arises not only from its fungicidal activity but also from amplification of host immunity, an effect primarily dependent on fungal susceptibility. This dual mode of action highlights a previously underappreciated role of echinocandins in shaping antifungal immunity and provides new mechanistic insight into drug-host–pathogen interactions during systemic candidiasis.

ABSTRACTBackgroundNitroxoline is an old antibiotic currently approved for the treatment of uncomplicated urinary tract infections. Its mode of action is based on the chelation of bivalent cations, such as zinc.ObjectivesAs zinc plays a central role in the metabolism of Aspergillus spp., we performed antifungal susceptibility testing against Nitroxoline using broth microdilution.MethodsOverall, 13 Aspergillus isolates were tested according to the EUCAST guidance document (Guinea et al. EUCAST, def. doc. 9.4, 2022) including two genetically proven Azole‐resistant strains.ResultsThe overall Minimal Inhibitory Concentration (MIC)50/90 was 0.5 mg/L.ConclusionsThese results correspond to excellent in vitro activity against Aspergillus spp.

Eosinophils are innate immune cells with central roles in allergy, parasitic diseases and multiple inflammatory conditions. Moreover, their role in host-pathogen interactions has been well characterized. However, the role of eosinophils during fungal infection is poorly defined. In this study, we delineate the importance of eosinophils during C. albicans systemic infections. C. albicans is promptly phagocytosed by human eosinophils, but growing hyphae escape this mechanism by releasing the fungal toxin candidalysin, which causes eosinophil membrane damage and cell death. Concomitantly, eosinophil mediators, notably major basic protein 1 (MBP-1), released during cytolysis, inhibits C. albicans growth and viability. Moreover, systemic candidiasis in genetic (Δdbl/GATA) or anti–IL-5–mediated depletion of eosinophils results in increased fungal burden and decreased survival. We here identified CD48 as a major receptor of eosinophils and possibly of other immune cells involved in the recognition of C. albicans via agglutinin-like sequence 6 (Als6). CD48 is important for protection in a model of systemic candidiasis as shown in CD48−/− mice and it binds clinical isolates of C. albicans. In conclusion, we have defined a protective role for eosinophils in vitro and in mouse C. albicans infections through CD48/Als6 host-pathogen interaction axis.

This first-in-human, single ascending dose study evaluated the safety, tolerability and pharmacokinetics (PK) of the decaprenylphosphoryl-β-D-ribose-2'-epimerase (DprE1) inhibitor BTZ-043. BTZ-043 was administered as an oral suspension at doses of 125, 250 and 500 mg along with placebo to healthy participants. Safety assessments included evaluation of laboratory parameters, vital signs, physical and neurological examination, and 12-lead ECG. Blood samples for PK assessment in plasma were collected over a 36 h post-dose period. PK parameters were calculated using non-compartmental analysis for parent BTZ-043, metabolites M1 and M2, and BTZ-043total (sum of BTZ-043 and M2) in plasma. Thirty participants completed the study. All administered BTZ-043 doses were safe and well tolerated. Nervous system disorders (dizziness and headache) and vascular disorders (hypertension and hot flush) were the most frequently reported adverse events (AEs). All AEs were mild or moderate. The parent compound BTZ-043 was rapidly metabolized to metabolite M2 (unknown activity), with median time to maximum concentration in plasma (t max) of 1.5 h (1-2 h). BTZ-043 and M2 had a short half-life. The second main inactive metabolite M1 showed a median t max of 7-8.5 h and a geometric mean half-life of 8.4-9.0 h. The increases in AUC and maximum concentration of drug in plasma (C max) of BTZ-043 were more than dose-proportional, and those of BTZ-043total were almost dose-proportional. No relevant differences in systemic exposures between males and females were observed. BTZ-043 was safe, well tolerated and underwent rapid absorption, metabolism and elimination, supporting further clinical development.

Pseudomonas syringae is a soil‐dwelling bacterium that exhibits remarkable niche adaptability, and it is known for its devastating impact as a plant pathogen. This bacterium has an outstanding capability to produce a wide array of biologically active natural products. P. syringae coexists with amoebal predators and fungal strains, which drives the production of secondary metabolites for predator evasion in addition to niche adaptation. In this study, we conducted a broad pangenomic analysis of 18 taxonomically distinct P. syringae strains, leading to the identification of 231 biosynthetic gene clusters (BGCs). Among these, nonribosomal peptide synthetases (NRPSs) were particularly abundant, indicating their potential significance within this ecological context. We discovered and elucidated the structures of two novel classes of bioactive compounds, the syrilipamides and chlorosecimides. Furthermore, a bioinformatic analysis enabled the identification of an undescribed halogenase, SecA, essential for the chlorination of secimide A. We observed that syrilipamides and secimides and in particular mixtures thereof, exhibit amoebicidal activities. Additionally, secimides showed selective antifungal activity. These findings provide valuable insights into the ecological roles of P. syringae natural products and highlight their potential for biotechnological and therapeutic applications.

Fungi are important and often underestimated human pathogens. Infections with fungi mostly originate from the environment, from soil or airborne spores. By contrast, Candida albicans, one of the most common and clinically important fungal pathogens, permanently exists in the vast majority of healthy individuals as a member of the human mucosal microbiota. Only under certain circumstances will these commensals cause infections. However, although the pathogenic behaviour and disease manifestation of C. albicans have been at the centre of research for many years, its asymptomatic colonization of mucosal surfaces remains surprisingly understudied. In this Review, we discuss the interplay of the fungus, the host and the microbiome on the dualism of commensal and pathogenic life of C. albicans, and how commensal growth is controlled and permitted. We explore hypotheses that could explain how the mucosal environment shapes C. albicans adaptations to its commensal lifestyle, while still maintaining or even increasing its pathogenic potential.

The total synthesis of Pseudomonas-derived cyclic lipodepsipeptide anikasin was achieved. Using a depsipeptide building block and balanced protecting groups on the branching d-allo-Thr residue, the synthesis was established semiautomatically on a synthesizer. Buffered deprotections minimized side reactions and afforded synthetic anikasin and its enantiomer. Biological activity studies indicated that anikasin's mode of action is directly resulting from its physicochemical properties.

Sustainable chemical production from C1 gaseous substrates, such as syngas or CO2/H2, can be achieved through gas fermentation. In gas fermentation, acetogenic bacteria are able to utilize oxidized inorganic carbon sources as the sole carbon source and electron acceptor, while reduced inorganic species are used as the electron donor. Clostridium ljungdahlii, a model acetogen, is only capable of reducing CO2 to acetate and ethanol, with H2 as electron donor. In order to expand the product profile of this bacterium, five alcohol acetyltransferases (AATs) from yeast were heterologously expressed in C. ljungdahlii to evaluate its potential to produce ethyl acetate. When growing on CO2 and H2, up to 7.38 ± 0.43mg/L of ethyl acetate were produced. Using fructose as the main carbon and energy source, up to 23.15 ± 1.28mg/L of ethyl acetate were produced. Ethanol and fumarate supplementation were able to boost ethyl acetate titers (up to 37.51 ± 9.44mg/L). Hence, ethyl acetate production was enabled in C.ljungdahlii at low titers, which could be explained by the high energetic cost of operation of AATs, and their shown promiscuity. However, we also show that this opens the door to more complex esterification reactions of higher added value biomolecules.

Combining biotechnology and chemistry strategies seems to be one of the main drivers to develop innovative and sustainable macromolecular architectures for the next decades, starting from renewable carbon sources, such as biomass and plastic wastes. Herein, microbially produced biobased precursors, namely esterified 3-(3-hydroxyalkanoyloxy)alkanoates (HAAs), averagely comprised of ten carbons each fatty acid, and polyol lipids (PL) mainly structured with 3,5-dihydroxydecanoic acids connected to a mannitol head group as the largest fraction (78%), have been used as building blocks to synthesize different urethane-based polymers and plasticizers as a proof of concept of this global approach. Polyurethanes (PU) were elaborated using HAAs and PL as chain extenders and then processed as films. The structure of these polyester-polyols significantly impacted the resulting properties. The hard segments (HS) on HAA-based PUs slightly increases from 40 to 46% and the asymmetrical disposal of aliphatic chains hindered regular organization, making all samples fully amorphous. Conversely, the chain’s entanglement benefited network cohesion. In contrast, chemically crosslinked PL-based PU can be processed as films with superior mechanical properties, despite having lower HS (33%). Additionally, plasticizers based on HAAs, and PL significantly increased the flexibility and elasticity of polyvinyl chloride (PVC). These findings suggest that such sustainable polyester-polyols offer valuable potential for developing sustainable PUs, meeting the requirements of a circular (bio)economy.

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015. Since its conception, MIBiG has been regularly updated to expand data coverage and remain up to date with innovations in natural product research. Here, we describe MIBiG version 4.0, an extensive update to the data repository and the underlying data standard. In a massive community annotation effort, 267 contributors performed 8304 edits, creating 557 new entries and modifying 590 existing entries, resulting in a new total of 3059 curated entries in MIBiG. Particular attention was paid to ensuring high data quality, with automated data validation using a newly developed custom submission portal prototype, paired with a novel peer-reviewing model. MIBiG 4.0 also takes steps towards a rolling release model and a broader involvement of the scientific community. MIBiG 4.0 is accessible online at https://mibig.secondarymetabolites.org/.