The choanoflagellate Salpingoeca rosetta is an important model system to study the evolution of multicellularity. In this study we developed a new, modular, and scalable synthesis of sulfonolipid IOR-1A (six steps, 27 % overall yield), which acts as bacterial inhibitor of rosette formation in S. rosetta . The synthesis features a decarboxylative cross-coupling reaction of a sulfonic acid-containing tartaric acid derivative with alkyl zinc reagents. Synthesis of 15 modified IOR-1A derivatives, including fluorescent and photoaffinity-based probes, allowed quantification of IOR-1A, localization studies within S. rosetta cells, and evaluation of structure-activity relations. In a proof of concept study, an inhibitory bifunctional probe was employed in proteomic profiling studies, which allowed to deduce binding partners in bacteria and S. rosetta . These results showcase the power of synthetic chemistry to decipher the biochemical basis of cell differentiation processes within S. rosetta .

Targeting the cellular sphingolipid metabolism is often discussed as a potential approach to treat associated human diseases such as cancer and Alzheimer's disease. Alternatively, it is also a possible target for the development of antifungal compounds, which are direly needed.

Sphingofungins belong to a group of structurally related sphingolipid inhibitors produced by fungi, which specifically inhibit serine palmitoyl transferases, enzymes catalyzing the initial step during sphingolipid biosynthesis. Sphingolipids are integral parts of the eukaryotic cell membrane, and disturbances in their homeostasis have been linked to various human diseases. It has been suggested that external interventions, via sphingolipid inhibitors, may represent a promising approach for alternative therapies. Here, we identified and elucidated the biosynthetic gene cluster responsible for the biosynthesis of sphingofungins B, C, and D in Aspergillus fumigatus. Moreover, in vitro analyses have shown that sphingofungin biosynthesis starts with the condensation of a C18 polyketide with the uncommon substrate aminomalonate. Furthermore, the investigations on sphingofungin E and F produced by Paecilomyces variotii pointed out that different aminomalonate derivatives are used as substrates for those chemical variants. This research boosts knowledge on the general biosynthesis of sphingolipid inhibitors in fungi.

We have analyzed the abundance of bacterial sulfonosphingolipids, including rosette-inducing factors (RIFs), in seven bacterial prey strains by using high-resolution tandem mass spectrometry (HRMS2 ) and molecular networking (MN) within the Global Natural Product Social Molecular Networking (GNPS) web platform. Six sulfonosphingolipids resembling RIFs were isolated and their structures were elucidated based on comparative MS and NMR studies. Here, we also report the first total synthesis of two RIF-2 diastereomers and one congener in 15 and eight synthetic steps, respectively. For the total synthesis of RIF-2 congeners, we employed a decarboxylative cross-coupling reaction to synthesize the necessary branched α-hydroxy fatty acids, and the Garner-aldehyde approach to generate the capnine base carrying three stereogenic centers. Bioactivity studies in the choanoflagellate Salpingoeca rosetta revealed that the rosette inducing activity of RIFs is inhibited dose dependently by the co-occurring sulfonosphingolipid sulfobacins D and F and that activity of RIFs is specific for isolates obtained from Algoriphagus.

Leucinostatins are fascinating natural substances, with high potency against many pathogens, but their acute toxicity has prevented therapeutic use. Michael Adams, Rainer Riedl, and co-workers demonstrate in the Research Article on page 15613 how these can be converted into synthetically more accessible and more selective antiprotozoal agents with broad efficacy and undetectable resistance.

AbstractLeucinostatin A ist eine der potentesten antiprotozoischen Verbindungen, die jemals beschrieben wurden, aber bisher war wenig über die Struktur‐Aktivitäts‐Beziehung (SAR) bekannt. Trypanosoma brucei wurde als Protozoen‐Modellorganismus verwendet, um synthetisch modifizierte Derivate zu testen. Dabei wurden die vereinfachten, aber gleichermaßen aktiven Verbindungen 2 (ZHAWOC6025) und 4 (ZHAWOC6027) identifiziert. Anschließend wurden Modifikationen in allen Teilen des Moleküls durchgeführt, um ein besseres SAR‐Verständnis zu erlangen. Die antiprotozoische SAR stimmte mit der SAR in Phospholipid‐Liposomen überein, wobei die Membranintegrität, das Durchlässigkeitsverhalten und die Dynamik untersucht wurden. Die antiprotozoale Wirkung der natürlichen und synthetischen Leucinostatine liegt in der Destabilisierung der inneren Mitochondrienmembran, wie durch Ultrastrukturanalyse, Elektronenmikroskopie und Mitochondrienfärbung gezeigt wurde. Eine subletale Langzeitexposition von T. brucei (200 Passagen) und ein siRNA‐Screening von 12′000 Mutanten zeigten keine Anzeichen einer Resistenzentwicklung gegenüber den synthetischen Derivaten.

Sphingofungins are fungal natural products known to inhibit the biosynthesis of sphingolipids which play pivotal roles in various cell functions. Here, we report a short and flexible synthetic approach towards the sphingofungin family. Key step of the synthesis was a decarboxylative cross-coupling reaction of chiral sulfinyl imines with a functionalized tartaric acid derivative, which yielded the core motif of sphingofungins carrying four consecutive stereocenters and a terminal double bond. Subsequent metathesis reaction allowed for the introduction of different side chains of choice resulting in a total of eight sphingofungins, including for the first time sphingofungin C (eight steps from commercially available protected tartaric acid with an overall yield of 6 %) and sphingofungin A (ten steps). All newly synthesized derivatives were tested for their antifungal, cell-proliferative and antiparasitic activity unraveling their structure–activity relations.

Leucinostatin A is one of the most potent antiprotozoal compounds ever described, but little was known on structure-activity relationships (SAR). We used Trypanosoma brucei as a protozoal model organism to test synthetically modified derivatives, resulting in simplified but equally active compounds 2 (ZHAWOC6025) and 4 (ZHAWOC6027), which were subsequently modified in all regions of the molecule to gain an in-depth SAR understanding. The antiprotozoal SAR matched SAR in phospholipid liposomes, where membrane integrity, leaking, and dynamics were studied. The mode of action is discussed based on a structure-activity analysis of derivatives in efficacy, ultrastructural studies in T. brucei, and artificial membrane models, mimicking membrane stability and membrane potential. The main site of antiprotozoal action of natural and synthetic leucinostatins lies in the destabilization of the inner mitochondrial membrane, as demonstrated by ultrastructural analysis, electron microscopy and mitochondrial staining. Long-time sublethal exposure of T. brucei (200 passages) and siRNA screening of 12'000 mutants showed no signs of resistance development to the synthetic derivatives.

Here, we applied and optimized a solid support (SP)-based Horner-Wadsworth-Emmons reagent to prepare SP-bound vinylogous amino acids. Subsequent SP-based peptide synthesis, global deprotection, and chemical modifications yielded 14 lipodipeptides carrying vinylogous amino acids, including the natural product barnesin A (1). Biological evaluation revealed that several synthesized derivatives show micromolar to nanomolar inhibitory activity against papain-like cysteine proteases, human cathepsin L, and rhodesain.

AbstractSphingolipide – polare Lipide, die Bestandteil von Zellmembranen sind und sich vom ungesättigten Aminoalkohol Sphingosin ableiten – wurden zwar im menschlichen Gehirn entdeckt, kommen aber in allen Lebensformen einschließlich Viren vor. Ihre Funktionen machen sie interessant für die Medikamentenforschung.

Many natural products are only produced in minor amounts and a full structural characterization is nearly impossible. In addition, many pharmaceutically interesting compounds are too toxic and need derivatisation to improve their pharmacological properties. Therefore, we are establishing synthetic strategies towards sphingoid-type natural products and functionalized lipids, which represent important signaling molecules in our ecological mdoel systems.

Cyclic peptides containing non-proteinogenic amino acids often exhibit a broad bioactivity spectrum and many have entered clinical trials with good prospects for drug development. We recently reported the discovery of six cyclic tetrapeptides, pseudoxylallemycins A-F (1-6), from a termite-associated Pseudoxylaria sp. X802. These compounds contain a rare O-homoallenyl-l-tyrosine moiety and show promising antimicrobial activity against the Gram-negative pathogenic bacterium Pseudomonas aeruginosa. To perform more detailed structure-activity studies, we pursued a precursor-directed diversification strategy. Herein, we report the purification, identification, and testing of 21 new pseudoxylallemycin derivatives.

The cover feature picture shows a fungus-growing termite nest in the South African savanna, the co-evolved antagonistic fungus of termites, Pseudoxylaria X802 that grows on natural fungus comb material, and isolated pseudoxylallemycins that contain a rare O-homoallenyl-l-tyrosine moiety. A precursor-directed diversification strategy with para-substituted unnatural amino acids resulted in the isolation of 21 new pseudoxylallemycin derivatives showing micromolar antibiotic activity. These results suggest that an unusual promiscuous non-ribosomal peptide synthase is responsible for their biosynthesis. Bifunctional pseudoxylallemycin derivatives were chemically modified for future target identification. More information the unusual natural products can be found in the full paper by C. Beemelmanns et al. on page 2307 in Issue 21, 2018 (DOI: 10.1002/cbic.201800503).

Despite the wealth of physiological knowledge and plentiful genomes available, only few natural products of anaerobic bacteria have been identified until today and even less have been linked to their biosynthetic gene cluster. Here, we analyzed a unique NRPS-PKS hybrid gene cluster from an anaerobic Epsilonproteobacterium ( Sulfurospirillum barnesii). Phylogenetic analysis of key biosynthetic genes, gene expression studies, and comparative metabolomics resulted in the identification of the first anoxically biosynthesized NRPS-PKS hybrid metabolite: a lipo-dipeptide with a vinylogous side chain, called barnesin A. The absolute structure was verified by a modular total synthesis, and barnesin and derivatives were found to have antimicrobial activity, as well as selective and nanomolar inhibitory activity, against pharmacological important cysteine proteases, such as cathepsin B.

Communication is essential for all domains of life. Bacteria use a plethora of small molecules to sense and orchestrate intra- and interspecies communication. Within this review, we will discuss different groups of signalling molecules, including autoinducers, virulence factors and morphogenic substances. On selected examples, we will shortly discuss their ecological roles and biosynthetic proposals. The major part of this review will focus on a systematic overview of the different synthetic methods applied towards the synthesis of signalling molecules and derivatives thereof. The described examples highlight the importance of organic synthetic method development and diversity-oriented total syntheses for structure verification, structure-function analysis and target identification.

AbstractNeue Strategien zur Bekämpfung von Antibiotikaresistenzen zu finden, ist eine der größten globalen Herausforderungen für die Gesundheitssysteme. In den letzten Jahrzehnten gab es eine drastische Zunahme an humanpathogenen Bakterien, die resistent gegen Antibiotika sind. Immer mehr Infektionen, die durch resistente Mikroorganismen verursacht werden, lassen sich nicht mehr mit konventionellen Behandlungen kurieren, und selbst Reserveantibiotika verlieren ihre Wirkung. Zusätzlich sind die Entwicklungsströme an neuen Antibiotika aus der pharmazeutischen Industrie in den letzten Jahrzehnten versiegt. Die Weltgesundheitsorganisation hat mit ihrem Aufruf “Combat drug resistance: no action today means no cure tomorrow” eine Zunahme der Forschungsaktivitäten auf diesem Gebiet stimuliert, und mehrere neue, vielversprechende Strategien zur Wiederherstellung antibiotischer Behandlungsoptionen konnten seitdem entwickelt werden.

Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last-resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled "Combat drug resistance: no action today means no cure tomorrow" triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.