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Lipopeptides represent a large group of microbial natural products that include important antibacterial and antifungal drugs and some of the most-powerful known biosurfactants. The vast majority of lipopeptides comprise cyclic peptide backbones N-terminally equipped with various fatty acyl moieties. The known compounds of this type are biosynthesized by nonribosomal peptide synthetases, giant enzyme complexes that assemble their products in a non–gene-encoded manner. Here, we report the genome-guided discovery of ribosomally derived, fatty-acylated lipopeptides, termed selidamides. Heterologous reconstitution of three pathways, two from cyanobacteria and one from an arctic, ocean-derived alphaproteobacterium, allowed structural characterization of the probable natural products and suggest that selidamides are widespread over various bacterial phyla. The identified representatives feature cyclic peptide moieties and fatty acyl units attached to (hydroxy)ornithine or lysine side chains by maturases of the GCN5-related N-acetyltransferase superfamily. In contrast to nonribosomal lipopeptides that are usually produced as congener mixtures, the three selidamides are selectively fatty acylated with C10, C12, or C16 fatty acids, respectively. These results highlight the ability of ribosomal pathways to emulate products with diverse, nonribosomal-like features and add to the biocatalytic toolbox for peptide drug improvement and targeted discovery.

The global rise of antibiotic resistance calls for new drugs against bacterial pathogens. A common approach is to search for natural compounds deployed by microbes to inhibit competitors. Here, we show that the iron-chelating pyoverdines, siderophores produced by environmental Pseudomonas spp., have strong antibacterial properties by inducing iron starvation and growth arrest in pathogens. A screen of 320 natural Pseudomonas isolates used against 12 human pathogens uncovered several pyoverdines with particularly high antibacterial properties and distinct chemical characteristics. The most potent pyoverdine effectively reduced growth of the pathogens Acinetobacter baumannii , Klebsiella pneumoniae, and Staphylococcus aureus in a concentration- and iron-dependent manner. Pyoverdine increased survival of infected Galleria mellonella host larvae and showed low toxicity for the host, mammalian cell lines, and erythrocytes. Furthermore, experimental evolution of pathogens combined with whole-genome sequencing revealed limited resistance evolution compared to an antibiotic. Thus, pyoverdines from environmental strains have the potential to become a new class of sustainable antibacterials against specific human pathogens. Despite the wide range of available antibiotics, a majority work through a similar mechanism, which enables some bacteria to become resistant to medical treatment. This means that the effectiveness of these molecules goes down and many curable infections may no longer be treatable. Collectively, antibiotic resistance poses a similar threat as other major diseases, such as malaria. One promising approach for discovering new antibiotics is to explore natural microbial communities for their ability to produce secondary metabolites with antimicrobial properties. Such metabolites are typically secreted by bacteria to compete with other community members for essential resources including nutrients. A well-known group of secreted metabolites are siderophores, which tightly sequester iron, a critical nutrient for bacterial growth. Each bacterial species produces its own set of specific siderophores, thus leading to a severe competition for iron. Vollenweider et al. investigated whether a group of siderophores secreted by Pseudomonas bacteria, called pyoverdines, are an effective antimicrobial agent against harmful human pathogens. Pyoverdines have a high affinity to iron and prevent competing bacteria from accessing the critical nutrient. This can inhibit their growth by starving them of iron. Vollenweider et al. treated resistant pathogens like Acinetobacter , Klebsiella and Staphylococcus grown in the laboratory, and found that pyoverdines significantly reduce their growth without the bacteria acquiring resistance. To test whether this treatment would work in a living infected animal, the group administered pyoverdines to moth larvae infected with the same pathogens and observed increased survival rates in the host. As iron is also required for human metabolism and found in the haemoglobin of red blood cells, Vollenweider, et al. confirmed pyoverdines do not retrieve iron from haemoglobin. Finally, in laboratory settings, pyoverdines did not negatively affect the growth of a human and a mouse cell line at low concentrations strong enough to inhibit the growth of pathogens. This approach is a promising example of adopting natural mechanisms that can have antimicrobial properties, and siderophores, in particular pyoverdines, may become a useful tool to treat otherwise incurable infections. Further research is needed in living mammalian models to confirm efficacy and safety of this novel antimicrobial treatment.

During the course of screening for new metabolites from basidiomycetes, we isolated and characterized five previously undescribed secondary metabolites, skeletocutins M–Q ( 1 – 5 ), along with the known metabolite tyromycin A ( 6 ) from the fruiting bodies of the polypore Skeletocutis sp. The new compounds did not exhibit any antimicrobial, cytotoxic, or nematicidal activities. However, compound 3 moderately inhibited the biofilm formation of Staphylococcus aureus ( S. aureus ), while compounds 3 and 4 performed moderately in the ʟ-leucine-7-amido-4-methylcoumarin (ʟ-Leu-AMC) inhibition assay. These compounds represent the first secondary metabolites reported to occur in the fruiting bodies by Skeletocutis . Interestingly, tyromycin A ( 6 ) was found to be the only common metabolite in fruiting bodies and mycelial cultures of the fungus, and none of the recently reported skeletocutins from the culture of the same strain were detected in the basidiomes.

A mycelial culture of the Kenyan basidiomycete Fomitiporia aethiopica was fermented on rice and the cultures were extracted with methanol. Subsequent HPLC profiling and preparative chromatography of its crude extract led to the isolation of five previously undescribed pregnenolone type triterpenes 1–5, for which we propose the trivial name aethiopinolones A–E. The chemical structures of the aethiopinolones were determined by extensive 1D- and 2D-NMR, and HRMS data analysis. The compounds exhibited moderate cytotoxic effects against various human cancer cell lines, but they were found devoid of significant nematicidal and antimicrobial activities.

During the course of our ongoing work to discover new inhibitors of biofilm formation of Staphylococcus aureus from fungal sources, we observed biofilm inhibition by cytochalasans isolated from cultures of the ascomycete Hypoxylon fragiforme for the first time. Two new compounds were purified by a bioassay-guided fractionation procedure; their structures were elucidated subsequently by nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS). This unexpected finding prompted us to test further cytochalasans from other fungi and from commercial sources for comparison. Out of 21 cytochalasans, 13 showed significant inhibition of Staphylococcus aureus biofilm formation at subtoxic levels. These findings indicate the potential of cytochalasans as biofilm inhibitors for the first time, also because the minimum inhibitory concentrations (MIC) are independent of the anti-biofilm activities. However, cytochalasans are known to be inhibitors of actin, making some of them very toxic for eukaryotic cells. Since the chemical structures of the tested compounds were rather diverse, the inclusion of additional derivatives, as well as the evaluation of their selectivity against mammalian cells vs. the bacterium, will be necessary as next step in order to develop structure-activity relationships and identify the optimal candidates for development of an anti-biofilm agent.

A mycelial culture of the African basidiomycete Echinochaete cf. brachypora was studied for biologically active secondary metabolites, and four compounds were isolated from its crude extract derived from shake flask fermentations, using preparative high-performance liquid chromatography (HPLC). The pure metabolites were identified using extensive nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS). Aside from the new metabolites 1-methoxyneomarinone (1) and (E)-3-methyl-5-(-12,13,14-trimethylcyclohex-10-en-6-yl)pent-2-enoic acid (4), the known metabolites neomarinone (2) and fumaquinone (4) were obtained. Such compounds had previously only been reported from Actinobacteria but were never isolated from the cultures of a fungus. This observation prompted us to evaluate whether the above metabolites may actually have been produced by an endosymbiontic bacterium that is associated with the basidiomycete. We have indeed been able to characterize bacterial 16S rDNA in the fungal mycelia, and the production of the metabolites stopped when the fungus was sub-cultured on a medium containing antibacterial antibiotics. Therefore, we have found strong evidence that compounds 1–4 are not of fungal origin. However, the endofungal bacterium was shown to belong to the genus Ralstonia, which has never been reported to produce similar metabolites to 1–4. Moreover, we failed to obtain the bacterial strain in pure culture to provide final proof for its identity. In any case, the current report is the first to document that polyporoid Basidiomycota are associated with endosymbionts and constitutes the first report on secondary metabolites from the genus Echinochaete.

During the course of a study on the functional biodiversity of the mycobiota inhabiting rainforests in Thailand, a fungal strain was isolated from a plant sample and shown to represent an undescribed species, as inferred from a combination of morphological and molecular phylogenetic methods. Molecular phylogenetic analyses, based on four DNA loci, revealed a phylogenetic tree with the newly generated sequences clustering in a separate branch, together with members of the Sulcatisporaceae (Pleosporales, Ascomycota). The Thai specimen morphologically resembled Neobambusicolastrelitziae in having pycnidial conidiomata with phialidic conidiogenous cells that produce both fusoid-ellipsoid macroconidia and subcylindrical microconidia. However, the new fungus, for which the name Pseudobambusicolathailandica is proposed, differs from N.strelitziae in having conidiomata with well-defined necks, the presence of globose to subglobose thick-walled cells adjacent to conidiomata and the production of chlamydospores in culture. When cultures of P.thailandica , growing on water agar, were confronted with Caenorhabditiselegans nematodes, worms approaching the fungal mycelia were killed. This observation gave rise to a study of its secondary metabolites and six novel and two known compounds were isolated from submerged cultures of P.thailandica . The structures of metabolites 1–6, for which the trivial names thailanones A–F are proposed, were elucidated using a combination of spectral methods, including extensive 1 and 2D NMR analysis and high resolution mass spectrometry. Compounds 4 and 8 showed strong nematicidal and weak antifungal activity, whereas all other tested compounds showed moderate to weak nematicidal activity but no significant effects in the serial dilution assay against various fungi and bacteria. Compounds 1 and 8 also inhibited growth of the pathogenic basidiomycete Phellinustremulae in a plate diffusion assay.

Treating infections organized in biofilms is a challenge due to the resistance of the pathogens against antibiotics and host immune cells. Many fungi grow in a wet environment, favorable for the growth of bacterial biofilms, and we speculated that fungi possess some strategies to control these bacterial biofilms. A fungus identified as Hypoxylon fragiforme, was collected in the Harz Mountains, Germany, and its mycelial culture was fermented in different culture media for 67 days to test its biological potential against bacterial biofilms. Sclerin, sclerin diacid and its 3-methyl monoester (methyl 1-(5-hydroxy-6-carboxylic-2,3,4-trimethylphenyl) propionate) are here described for the first time from this fungus. Sclerin and its diacid interfered with the biofilm formation of the pathogen Staphylococcus aureus, inhibiting 86% and 80% of the biofilm at 256 μg mL−1, respectively, but not killing the bacterium. Interestingly, the monomethylester of sclerin diacid was inactive. Although these compounds did not possess any activity against a pre-formed biofilm, they prevented its formation at subtoxic concentrations. Furthermore, sclerin and its diacid displayed a high specificity against Staphylococcus aureus, indicating a good strategy against pathogenic biofilms when combined with antibiotics.

The global rise of antibiotic resistance calls for new drugs against bacterial pathogens. A common approach is to search for natural compounds deployed by microbes to inhibit competitors. Here, we show that the iron-chelating pyoverdines, siderophores produced by environmental Pseudomonas spp., have strong antibacterial properties by inducing iron starvation and growth arrest in pathogens. A screen of 320 natural Pseudomonas isolates used against 12 human pathogens uncovered several pyoverdines with particularly high antibacterial properties and distinct chemical characteristics. The most potent pyoverdine effectively reduced growth of the pathogens Acinetobacter baumannii , Klebsiella pneumoniae, and Staphylococcus aureus in a concentration- and iron-dependent manner. Pyoverdine increased survival of infected Galleria mellonella host larvae and showed low toxicity for the host, mammalian cell lines, and erythrocytes. Furthermore, experimental evolution of pathogens combined with whole-genome sequencing revealed limited resistance evolution compared to an antibiotic. Thus, pyoverdines from environmental strains have the potential to become a new class of sustainable antibacterials against specific human pathogens. Despite the wide range of available antibiotics, a majority work through a similar mechanism, which enables some bacteria to become resistant to medical treatment. This means that the effectiveness of these molecules goes down and many curable infections may no longer be treatable. Collectively, antibiotic resistance poses a similar threat as other major diseases, such as malaria. One promising approach for discovering new antibiotics is to explore natural microbial communities for their ability to produce secondary metabolites with antimicrobial properties. Such metabolites are typically secreted by bacteria to compete with other community members for essential resources including nutrients. A well-known group of secreted metabolites are siderophores, which tightly sequester iron, a critical nutrient for bacterial growth. Each bacterial species produces its own set of specific siderophores, thus leading to a severe competition for iron. Vollenweider et al. investigated whether a group of siderophores secreted by Pseudomonas bacteria, called pyoverdines, are an effective antimicrobial agent against harmful human pathogens. Pyoverdines have a high affinity to iron and prevent competing bacteria from accessing the critical nutrient. This can inhibit their growth by starving them of iron. Vollenweider et al. treated resistant pathogens like Acinetobacter , Klebsiella and Staphylococcus grown in the laboratory, and found that pyoverdines significantly reduce their growth without the bacteria acquiring resistance. To test whether this treatment would work in a living infected animal, the group administered pyoverdines to moth larvae infected with the same pathogens and observed increased survival rates in the host. As iron is also required for human metabolism and found in the haemoglobin of red blood cells, Vollenweider, et al. confirmed pyoverdines do not retrieve iron from haemoglobin. Finally, in laboratory settings, pyoverdines did not negatively affect the growth of a human and a mouse cell line at low concentrations strong enough to inhibit the growth of pathogens. This approach is a promising example of adopting natural mechanisms that can have antimicrobial properties, and siderophores, in particular pyoverdines, may become a useful tool to treat otherwise incurable infections. Further research is needed in living mammalian models to confirm efficacy and safety of this novel antimicrobial treatment.