Chemical investigation of the fungal endophyte Xylaria sp. isolated from leaves of Moringa oleifera, collected in Cameroon, resulted in the previously undescribed 10-membered macrolide, and two known natural products. The structures of the xylatolides A and B were unambiguously identified by their mass spectra and by extensive 1D and 2D NMR spectroscopic analysis, featuring a 10-membered lactone core structure with oxygenated substituents and an unsubstituted 10-alkyl chain presenting seven carbon atoms. Compounds were screened for their cytotoxic potential against the human HepG2 hepatocellular carcinoma cells and HCT-116 cells (human colon carcinoma cell line). Moreover, the isolated compounds were also assayed against a small panel of sensitive strains including the bacterial species Escherichia coli, Staphylococcus aureus, and Mycobacterium tuberculosis as well as against the fungal species Candida albicans. However, no significant activities were found.

The OSMAC (one strain many compounds) concept is a cultivation-based approach to increase the diversity of secondary metabolites in microorganisms. In this study, we applied the OSMAC-approach to the endophytic fungus Trichocladium sp. by supplementation of the cultivation medium with 2.5% phenylalanine. This experiment yielded five new compounds, trichocladiol (1), trichocladic acid (2), colletodiolic acid (3), colletolactone (4) and colletolic acid (5), together with five previously described ones (6-10). The structures were elucidated via comprehensive spectroscopic measurements, and the absolute configurations of compound 1 was elucidated by using TDDFT-ECD calculations. For formation of compounds 3-5, a pathway based on colletodiol biosynthesis is proposed. Compound 6 exhibited strong antibacterial activity against methicillin-resistant Staphylococcus aureus with a minimal inhibitory concentration (MIC) of 0.78 μM as well as a strong cytotoxic effect against the human monocytic cell line THP1 with an IC50 of 0.7 μM. Compound 8 showed moderate antibacterial activity against Mycobacterium tuberculosis with a MIC of 25 μM and a weak cytotoxic effect against THP1 cells with an IC50 of 42 μM.

Spread of antimicrobial resistances urges a need for new drugs against Mycobacterium tuberculosis (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.

Clonostachys rosea is a fungus widely distributed on Earth and has a high capacity to adapt to complex environments in soil, plants, or sea. It is an endophyte that can be used as a potential biocontrol agent to protect plants from pathogenic fungi, nematodes, and insects. However, the spectrum of secondary metabolites produced by C. rosea has only scarcely been studied. In the present study, eight new phenalenones, asperphenalenones F-M (1-8), together with two known derivatives, asperphenalenones E and B (9 and 10), were isolated from the axenic rice culture of this fungus. The structures of the new compounds were elucidated by nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, electronic circular dichroism, and gas chromatography-mass spectrometry analyses. Asperphenalenones J-M (5-8) are unusual phenalenone adducts that are conjugated to diterpenoid glycosides. Asperphenalenones F and H showed moderate antibacterial activity against methicillin-resistant Staphylococcus aureus, with minimal inhibitory concentrations of 12.5 and 25 μM, respectively. Asperphenalenone B exhibited low antiviral activity against the human immunodeficiency virus replication. Furthermore, asperphenalenones F and H exhibited low cytotoxicity against Jurkat cells, while all other compounds were devoid of cytotoxicity.

A new siderophore, serratiochelin D (1), was isolated from a soil-derived, non-pigmented strain of Serratia marcescens along with two previously reported siderophores, serratiochelins A and B. Siderophores were obtained after cultivating the bacterium in an iron-deficient medium, and the chemical structures were elucidated based on HPLC-UV, mass spectrometry, and extensive 1D and 2D NMR spectral analyses. The iron-chelating, growth-promoting, and cytotoxic activities were evaluated using standard methods. Serratiochelin D (1) demonstrated xenosiderophoric activity by promoting the growth of Staphylococcus aureus, Acinetobacter baumannii, and Mycobacterium tuberculosis in iron-limited media and thus has the potential to be developed into a sideromycin against pathogens in these genera and other MDR bacteria.

Co-culturing of fungi and bacteria proved to be an efficient tool for inducing the expression of silent biosynthetic gene clusters (BGCs). This study reports the isolation of a new meroterpenoid derivative, andrastin I (1), from a marine-derived fungus Penicillium ochrochloron. Co-cultivation of the fungus with Bacillus subtilis yielded another new natural product, a butyrolactone congener, ochrochloronic acid (2) and the known fungal metabolite striatisporolide A. Chemical structures of all isolated compounds were confirmed based on HRESIMS as well as, extensive 1D and 2D NMR spectral analyses. Absolute configuration of 1 was established by comparing the experimental ECD with those of known analogues. Results of this study highlight the potential of marine fungi as sources of new natural products and demonstrates the efficiency of fungal-bacterial co-cultivation as a promising tool to induce the immense biosynthetic capabilities of silent BGCs.

Toxoplasma gondii is an apicomplexan pathogen able to infect a wide range of warm-blooded animals, including humans, leading to toxoplasmosis. Current treatments for toxoplasmosis are associated with severe side-effects and a lack efficacy to eradicate chronic infection. Thus, there is an urgent need for developing novel, highly efficient agents against toxoplasmosis with low toxicity. For decades, natural products have been a useful source of novel bioactive compounds for the treatment of infectious pathogens. In the present study, we isolated eight natural products from the crude extract of the endophytic fungus Paraboeremia selaginellae obtained from the leaves of the plant Philodendron monstera. The natural products were tested for inhibiting Toxoplasma gondii proliferation, and their cytotoxicity was evaluated in different human cell lines. Six natural products showed antitoxoplasma activity with low or no cytotoxicity in human cell lines. Together, these findings indicate that biphenyl ethers, bioxanthracenes, and 5S,6S-phomalactone from P. selaginellae are potential candidates for novel anti-toxoplasma drugs.

Purpose: To evaluate the xenosiderophoric properties of siderophores produced by Serratia marcescens towards Acinetobacter baumannii, Staphylococcus aureus and Mycobacterium tuberculosis. Methods: A non-pigmented strain of S. marcescens was isolated from soil after cultivation in iron limited LB medium. The isolate was identified using both biochemical and 16S rDNA molecular phylogenetic analyses. The bacterial secondary metabolites were extracted after solid state fermentation in sterile rice medium. The extract was separated using chromatography, and the resulting compounds were analyzed by mass spectrometry and nuclear magnetic resonance spectroscopy. The iron-chelating, growth-promoting and cytotoxic activities of the compounds were determined using standard protocols. Results: Two siderophore compounds (serratiochelins A and B) were isolated from the fermentation extract of S. marcescens. Characteristic of siderophores, serratiochelins A and B exhibited varying degrees of iron-chelating activities. The compounds displayed xenosiderophoric properties by supporting the growth of A. baumannii and M. tuberculosis in iron-limited media. In addition, the siderophores displayed cytotoxic activity against human cells, with serratiochelin A showing the higher activity with IC50 of 3.20 and 6.26 mu M against THP-1 and HEK-293 cells, respectively. Conclusion: This study demonstrates the isolation of serratiochelins A and B from a soil-derived non pigmented strain of S. marcescens. The siderophores support the growth of A. baumannii and M. tuberculosis, and thus, have prospects for development as sideromycins against these multidrug resistant (MDR) organisms.