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How to Completely Squeeze a Fungus-Advanced Genome Mining Tools for Novel Bioactive Substances.

ABSTRACT: Fungal species have the capability of producing an overwhelming diversity of bioactive substances that can have beneficial but also detrimental effects on human health. These so-called secondary metabolites naturally serve as antimicrobial "weapon systems", signaling molecules or developmental effectors for fungi and hence are produced only under very specific environmental conditions or stages in their life cycle. However, as these complex conditions are difficult or even impossible to mimic in laboratory settings, only a small fraction of the true chemical diversity of fungi is known so far. This also implies that a large space for potentially new pharmaceuticals remains unexplored. We here present an overview on current developments in advanced methods that can be used to explore this chemical space. We focus on genetic and genomic methods, how to detect genes that harbor the blueprints for the production of these compounds (i.e., biosynthetic gene clusters, BGCs), and ways to activate these silent chromosomal regions. We provide an in-depth view of the chromatin-level regulation of BGCs and of the potential to use the CRISPR/Cas technology as an activation tool.

SUBMITTER: Schuller A

PROVIDER: S-EPMC9505985 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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How to Completely Squeeze a Fungus-Advanced Genome Mining Tools for Novel Bioactive Substances.

Schüller Andreas A Studt-Reinhold Lena L Strauss Joseph J

Pharmaceutics 20220831 9

Fungal species have the capability of producing an overwhelming diversity of bioactive substances that can have beneficial but also detrimental effects on human health. These so-called secondary metabolites naturally serve as antimicrobial "weapon systems", signaling molecules or developmental effectors for fungi and hence are produced only under very specific environmental conditions or stages in their life cycle. However, as these complex conditions are difficult or even impossible to mimic in ...[more]

PMID: 36145585

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Project description:BackgroundAntibiotic resistance in bacteria spreads quickly, overtaking the pace at which new compounds are discovered and this emphasizes the immediate need to discover new compounds for control of infectious diseases. Terrestrial bacteria have for decades been investigated as a source of bioactive compounds leading to successful applications in pharmaceutical and biotech industries. Marine bacteria have so far not been exploited to the same extent; however, they are believed to harbor a multitude of novel bioactive chemistry. To explore this potential, genomes of 21 marine Alpha- and Gammaproteobacteria collected during the Galathea 3 expedition were sequenced and mined for natural product encoding gene clusters.ResultsIndependently of genome size, bacteria of all tested genera carried a large number of clusters encoding different potential bioactivities, especially within the Vibrionaceae and Pseudoalteromonadaceae families. A very high potential was identified in pigmented pseudoalteromonads with up to 20 clusters in a single strain, mostly NRPSs and NRPS-PKS hybrids. Furthermore, regulatory elements in bioactivity-related pathways including chitin metabolism, quorum sensing and iron scavenging systems were investigated both in silico and in vitro. Genes with siderophore function were identified in 50% of the strains, however, all but one harboured the ferric-uptake-regulator gene. Genes encoding the syntethase of acylated homoserine lactones were found in Roseobacter-clade bacteria, but not in the Vibrionaceae strains and only in one Pseudoalteromonas strains. The understanding and manipulation of these elements can help in the discovery and production of new compounds never identified under regular laboratory cultivation conditions. High chitinolytic potential was demonstrated and verified for Vibrio and Pseudoalteromonas species that commonly live in close association with eukaryotic organisms in the environment. Chitin regulation by the ChiS histidine-kinase seems to be a general trait of the Vibrionaceae family, however it is absent in the Pseudomonadaceae. Hence, the degree to which chitin influences secondary metabolism in marine bacteria is not known.ConclusionsUtilizing the rapidly developing sequencing technologies and software tools in combination with phenotypic in vitro assays, we demonstrated the high bioactive potential of marine bacteria in an efficient, straightforward manner - an approach that will facilitate natural product discovery in the future.

Project description:Humic substances (HS) are complex natural mixtures comprising a large variety of compounds produced during decomposition of decaying biomass. The molecular composition of HS is extremely diverse as it was demonstrated with the use of high resolution mass spectrometry. The building blocks of HS are mostly represented by plant-derived biomolecules (lignins, lipids, tannins, carbohydrates, etc.). As a result, HS show a wide spectrum of biological activity. Despite that, HS remain a 'biological activity black-box' due to unknown structures of constituents responsible for the interaction with molecular targets. In this study, we investigated the antiviral activity of eight HS fractions isolated from peat and coal, as well as of two synthetic humic-like materials. We determined molecular compositions of the corresponding samples using ultra-high resolution Fourier-transform ion cyclotron resonance mass-spectrometry (FTICR MS). Inhibitory activity of HS was studied with respect to reproduction of tick-borne encephalitis virus (TBEV), which is a representative of Flavivirus genus, and to a panel of enteroviruses (EVs). The samples of natural HS inhibited TBEV reproduction already at a concentration of 1 µg/mL, but they did not inhibit reproduction of EVs. We found that the total relative intensity of FTICR MS formulae within elemental composition range commonly attributed to flavonoid-like structures is correlating with the activity of the samples. In order to surmise on possible active structural components of HS, we mined formulae within FTICR MS assignments in the ChEMBL database. Out of 6502 formulae within FTICR MS assignments, 3852 were found in ChEMBL. There were more than 71 thousand compounds related to these formulae in ChEMBL. To support chemical relevance of these compounds to natural HS we applied the previously developed approach of selective isotopic exchange coupled to FTICR MS to obtain structural information on the individual components of HS. This enabled to propose compounds from ChEMBL, which corroborated the labeling data. The obtained results provide the first insight onto the possible structures, which comprise antiviral components of HS and, respectively, can be used for further disclosure of antiviral activity mechanism of HS.

Project description:Fungal metabolites, proteins, and enzymes have been rich sources of therapeutics so far. Therefore, in this study, the hypha extract of a newly identified noble fungus (Alternaria sp. with NCBI Accession number: MT982648) was used to synthesize silver nanoparticles (F-AgNPs) to utilize against bacteria, fungi, and lung cancer. F-AgNPs were characterized by using physical techniques, including UV-visible spectroscopy, zeta potential, DLS, XRD, TEM, and HR-TEM. The particles were found to be polydispersed and quasi-spherical in shape under TEM. They had an average size of ~15 nm. The well dispersed particles were found to have consistent crystallinity with cubic phase geometry under XRD and HR-TEM. The presence of different functional groups on the surfaces of biosynthesized F-AgNPs was confirmed by FTIR. The particle distribution index was found to be 0.447 with a hydrodynamic diameter of ~47 d.nm, and the high value of zeta potential (-20.3 mV) revealed the stability of the nanoemulsion. These particles were found to be active against Staphylococcus aureus (multidrug resistance-MDR), Klebsiella pneumonia, Salmonella abony, and Escherichia coli (MDR) with MIC50 10.3, 12.5, 22.69, and 16.25 µg/mL, respectively. Particles also showed inhibition against fungal strains, including A. flavus, A. niger, T. viridens, and F. oxysporium. Their inhibition of biofilm formation by the same panel of bacteria was also found to be very promising and ranged from 16.66 to 64.81%. F-AgNPs also showed anticancer potential (IC50-21.6 µg/mL) with respect to methotrexate (IC50-17.7 µg/mL) against lung cancer cell line A549, and they did not result in any significant inhibition of the normal cell line BEAS-2. The particles were found to alter the mitochondrial membrane potential, thereby disturbing ATP synthesis and leading to high ROS formation, which are responsible for cell membrane damage and release of LDH, intracellular proteins, lipids, and DNA. A high level of ROS also elicits pro-inflammatory signaling cascades that lead to programmed cell death by either apoptosis or necrosis.

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How to Completely Squeeze a Fungus-Advanced Genome Mining Tools for Novel Bioactive Substances.

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How to Completely Squeeze a Fungus-Advanced Genome Mining Tools for Novel Bioactive Substances.

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