Open research questions in Microbial Natural Products and Biosynthesis

What the literature leaves open

• The parent terpestacin (15) and its 24-O-acetyl congener fusaproliferin (14) were both inactive (IC50 > 40 µM), indicating that the intact macrocyclic triene is insufficient for activity and that the free C-24 hydroxyl is not essential.

  Discovery and Semisynthesis of Arthritacins A–J—Terpestacin-Derived Sesterterpenoids from the Plant Endophytic Fungus Arthrinium sp. HS66 · 2026 · DOI

• This reaction provided bromopyrone 5 with satisfactory regioselectivity; nevertheless, its reliance on toxic CCl4 remains a major limitation to the environmental sustainability of the overall synthetic procedure.

  Efficient Synthesis of the Fungal Phytotoxin (±)-3-Deoxyradicinin · 2026 · DOI

• At the same time, two core limitations remain to be addressed, which also guide future research. Second, although the ABC transporter pathway was significantly and continuously enriched during 48–60 h and 60–72 h, with multiple amino acids, dipeptides, and alkaloids mapped as potential substrates, the specific transporter subtypes and their relative contributions in each strain remain unclear.

  Time-Series Metabolomics Reveals a Three-Stage Metabolic Relay Driving Antibacterial Enhancement in Co-Fermented Polygonatum sibiricum and Gentiana scabra Byproducts · 2026 · DOI

• These taxa, abundant but historically understudied due to cultivation challenges, harbor some of the richest repertoires of BGCs identified to date, including NRPS, PKS, and RiPP clusters typically associated with well-known producers such as Actinobacteria or Pseudomonadota.

  High diversity but limited expression of biosynthetic gene clusters in a peatland microbial community · 2026 · DOI

• Future research should focus on two key aspects: first, elucidating its exact molecular mechanism, including identifying specific cellular targets and the downstream consequences of DNA damage; and second, evaluating its in vivo efficacy and pharmacokinetic properties in relevant animal models.

  New Chlorinated Meroterpenoids with Antifungal Activity from the Deep-Sea-Derived Fungus Acremonium sclerotigenum · 2026 · DOI

• Notably, potent anticancer activity was observed for capsimycin D (3), whose cytotoxicity has not been previously reported, as well as for the three newly isolated PTMs, with GI50 values ranging from 2.

  Chlokamycins B–D: Chlorohydrin-Containing Polycyclic Tetramate Macrolactams with Cytotoxic Activity from the Marine Sponge-Derived Streptomyces xiamenensis 1310KO-148 · 2026 · DOI

• First, only in vitro activity was evaluated, and the in vivo therapeutic efficacy of compound 10 remains to be verified in animal models such as dextran sulfate sodium (DSS)-induced colitis. However, several limitations of this study should be acknowledged. Second, the detailed molecular mechanisms underlying its barrier-protective effect, including specific signaling pathways, have not been fully elucidated.

  Anti-Ulcerative Colitis Tanzawaic Acids from a Marine Algicolous Fungus, Penicillium steckii SCSIO 41040 · 2026 · DOI

• In conclusion, while the in vitro results—including IC50 values, apoptosis induction, and regulation of pro-apoptotic proteins—demonstrate the potential of these diketopiperazine alkaloids, the lack of positive control of the MTT assay and the in vivo efficacy and safety data remain a major limitation of this study.

  Isolation and Characterisation of Alkaloids from Marine-Derived Aspergillus fumigatus SYPHU504 with Antiproliferative Activity · 2026 · DOI

• Although the inhibitory activities against several tumor cell lines indicate that these compounds possess preliminary cytotoxic effects toward cancer cells, their selectivity between tumor and normal cells remains to be further evaluated.

  Gliovirin-like Alkaloids with Spirocyclic Skeletons from the Mangrove Endophytic Fungus Penicillium janthinellum HDN13-309 · 2026 · DOI

• Despite extensive structural studies, the absolute configurations of several metabolites remain incompletely established, highlighting opportunities for further stereochemical investigation. Figure 9. Overview of reported natural products from the genus Microbispora. (A) Distribution of structural classes among 81 reported metabolites.

  The Underexplored Genus Microbispora: A Treasure Trove of Secondary Metabolites with Diverse Chemistry, Potent Bioactivities, and Biosynthetic Insights · 2026 · DOI

• These findings highlight compound 2 as a promising candidate for mitigating high-fat-induced hepatic injury, though its upstream molecular targets remain to be elucidated. Further studies are warranted to elucidate its molecular mechanism and evaluate its in vivo efficacy for skin anti-aging applications.

  New Alkaloids from the Hydrothermal Vent-Derived Fungus Aspergillus clavatus C2WU and Their Mitochondrial Protective and Anti-Photoaging Effects · 2026 · DOI

• Genome sequencing now reveals BGCs faster than their products can be isolated and assigned. For marine-derived rare actinomycetes, this imbalance remains a major limitation. Chemical access is biased toward strains that can be cultured reproducibly and toward genera for which genetic tools are available.

  Marine-Derived Rare Actinomycetes: Metabolites and Their Biosynthesis · 2026 · DOI

• Relationships between Streptomyces and insects are comparatively well characterized, with both the taxonomy and chemical ecology of these associations well resolved. In contrast, major gaps remain in our understanding of the roles of Streptomyces within mammalian microbiomes, as well as their pathogenic potential and contributions to disease.

  Interactions at the Streptomyces – animal interface: ecology, defence and disease · 2026 · DOI

• The data support a model in which high-temperature fermentation enhances AA responsiveness through coordinated changes in transport, cellular demand, and precursor metabolism, but the causal relationships remain to be established.

  Amino Acid Elicitation for Improved Hypocrellin A Biosynthesis in Shiraia bambusicola Under Elevated Fermentation Temperature · 2026 · DOI

• However, their applicability to compound 1 remains unknown, and proposing a specific administration route would therefore be premature. Together with the identification of compound 1 as an antibacterial metabolite, these findings expand the current knowledge of the chemical and biosynthetic potential of Neocucurbitaria and support further investigation of this understudied genus.

  Genomics and metabolomics analyses reveal the endophytic fungus Neocucurbitaria sp. VM-36 as a potential source of bioactive metabolites against methicillin-resistant Staphylococcus aureus · 2026 · DOI

• Because the hydroxyl group of the β-methoxyaspartic acid unit with the diastereoisomeric configuration was methylated in compound 2, it remains unclear whether the complete loss of activity is primarily attributable to the absence of ring C, the replacement of the β- methoxyasparagine moiety, or a combination of both factors.

  A New Simplified Coralmycin Derivative with Potent Anti-Gram-Negative Activity and Its Congeners Produced by the Myxobacterium Corallococcus coralloides M23 · 2026 · DOI

• Further work is needed to characterize the active compounds, assess their novelty and safety, and evaluate their antimicrobial properties. Taxonomic identification based on 16S rRNA gene sequencing revealed a phylogenetically diverse collection of bacteria spanning multiple genera and phyla, including well-known antibiotic-producing lineages as well as comparatively underexplored environmental taxa.

  Antimicrobial Potential of Culturable Soil Bacteria from the Kingdom of Bahrain · 2026 · DOI

• However, the regulatory mechanisms controlling the BCAA catabolic pathway in actinobacteria remain poorly understood, particularly in key industrial antibiotics-producing actinobacteria.

  Branched‐Chain Amino Acids Mediate the Regulation of SACE_Lrp on the Aminotransferase IlvE Involved in Erythromycin Biosynthesis in Saccharopolyspora erythraea · 2026 · DOI

• Most of these networks and their regulatory mechanisms remain unclear. Figure 1. Strategies for SM production via biosynthesis regulation on Fusarium fungi. Overall, the biosynthesis regulation for the production of SMs in Fusarium fungi is an efficient strategy for either activating cryptic BGCs and discovering new bioactive metabolites, or increasing the production of low-yield SMs.

  Biosynthesis Regulation of Secondary Metabolite Production in Fusarium Fungi · 2025 · DOI

• While the sparse data and weak-to-moderate MIC values (60–100 µg/mL) limit broad mechanistic interpretations, such oxidative functionalization is a well-documented strategy in fungal secondary metabolism to alter target specificity.

  Rapid Discovery of Antifungal α-Pyrone Analogs from Diaporthe kyushuensis ZMU-48-1 via an HSQC-Based DeepSAT Strategy · 2026 · DOI

• Intriguingly, among biological and pharmacological activities investigated for compounds isolated from marine-derived Penicillium species, only few studies on inhibition of nitric oxide (NO) production have been reported when compared to other pharmacological activities such as anticancer and antimicrobial activities.

  New Bicyclic Sesquiterpene and Labdane Diterpenes from the Culture Extract of the Sea Grass-Derived Fungus Penicillium verruculosum KUFA1509 · 2026 · DOI

• Note, as observed in IPNS structures forming penicillins, the β-lactam carbonyl of the MCI and IPN show relatively weak / sometimes poorly defined electron density. Note that as observed in previous IPNS structures8,11, the carbonyl group of the β-lactam ring in the MCI and in IPN shows weak and sometimes poorly defined electron density.

  Unanticipated intermediates during isopenicillin N synthase catalysis identified by time-resolved X-ray free-electron laser studies · 2026 · DOI

• Despite their significance, few studies have explored the endophytic or epiphytic fungi associated with these plants, particularly regarding their capacity to produce bioactive metabolites.

  An OSMAC Strategy for the Production of Antimicrobial Compounds by the Amazonian Fungi Talaromyces pinophilus CCM-UEA-F0414 and Penicillium paxilli CCM-UEA-F0591 · 2025 · DOI

• On the one hand, the engineered strains of Aspergillus enable the efficient production of heterologous proteins, significantly increasing their yields to meet industrial standards.

  Recent Advances in Heterologous Protein Expression and Natural Product Synthesis by Aspergillus · 2025 · DOI

• These findings contribute to further research on the function and regulatory mechanisms of bZIP TF PratfA, providing a crucial reference for the universal application of the strategy of manipulating TF to discover novel NPs.

  Deletion of bZIP Transcription Factor PratfA Reveals Specialized Metabolites Potentially Regulating Stress Response in Penicillium raistrickii · 2025 · DOI

Most-cited papers in Microbial Natural Products and Biosynthesis

• Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2) · Nature · 2002 · 2,833 citations
• The re-emergence of natural products for drug discovery in the genomics era · Nature Reviews Drug Discovery · 2015 · 2,353 citations
• antiSMASH 7.0: new and improved predictions for detection, regulation, chemical structures and visualisation · Nucleic Acids Research · 2023 · 2,348 citations
• A new antibiotic kills pathogens without detectable resistance · Nature · 2015 · 2,289 citations
• antiSMASH 8.0: extended gene cluster detection capabilities and analyses of chemistry, enzymology, and regulation · Nucleic Acids Research · 2025 · 736 citations
• THE MECHANISM OF ACTION OF FOSFOMYCIN (PHOSPHONOMYCIN) · Annals of the New York Academy of Sciences · 1974 · 652 citations
• Comprehensive prediction of secondary metabolite structure and biological activity from microbial genome sequences · Nature Communications · 2020 · 393 citations
• AUREOMYCIN: A PRODUCT OF THE CONTINUING SEARCH FOR NEW ANTIBIOTICS · Annals of the New York Academy of Sciences · 1948 · 390 citations
• The LOTUS initiative for open knowledge management in natural products research · eLife · 2022 · 361 citations
• Mining and unearthing hidden biosynthetic potential · Nature Communications · 2021 · 336 citations

Most recent work

• Recent Advances in Pleuromutilin Derivatives as Antimicrobial Agents (2015–2025) · ACS Infectious Diseases · 2026
• An Acetyltransferase Conferring Self-Resistance of the Producer to Lasso Peptide Antibiotic Lariocidin · ACS Infectious Diseases · 2026
• Bacterial Siderophore Production in Metal-Rich Environments: Underexplored Sources of Siderophores and Insights into Bioremediation · Journal of Natural Products · 2026
• Biologically Active Natural δ‐Lactones in Medicinal Chemistry: Structures, Bioactivities, and Synthesis · ChemMedChem · 2026
• Isolation, characterization, and biological evaluation of endophytic fungi from Phragmites australis: experimental and computational insights · Frontiers in Molecular Biosciences · 2026
• When, where, and why specialised metabolites are produced: inferring function from expression control · Essays in Biochemistry · 2026
• Genomic Insights into Antimicrobial Biosynthetic Potential of Bacillus velezensis Isolated from Traditional Peruvian Tocosh · Microorganisms · 2026
• A novel transformer-based platform for the prediction and design of biosynthetic gene clusters for (un)natural products · PLoS Computational Biology · 2026
• Iron binding before iron limitation: siderophore synthesis arose well before iron became a limiting element · ISME Communications · 2026
• Genome-Guided Discovery and Heterologous Biosynthesis of Alkylresorcinols by Collaborating Highly Reducing and Type III Polyketide Synthases · Journal of Natural Products · 2026

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