Open research questions in Microbial Natural Products and Biosynthesis

What the literature leaves open

• The need for novel bioactive compounds to address antimicrobial resistance. The underexplored potential of endophytic fungi as a source of bioactive compounds.

  The endophyte Fusarium oxysporum 3RR genome analysis identifies bioactive compounds targeting biofilm formation · 2026 · DOI

• Endophytic fungi, with their remarkable metabolic versatility and adaptation to diverse ecological niches, represent a promising, yet underexplored, reservoir of such mol- ecules (Manganyi and Ateba, 2020; Silva et al.

  The endophyte Fusarium oxysporum 3RR genome analysis identifies bioactive compounds targeting biofilm formation · 2026 · DOI

• Despite its scale, the collection reveals how much microbial biosynthetic diversity remains unexplored.

  BGC Atlas v2: biosynthetic gene clusters with taxonomic and environmental context at scale · 2026 · DOI

• The metabolomic capabilities of this phylum remain poorly characterized, with few experimentally confirmed metabolites described.

  Tryptophan-driven metabolomic shift in Acidobacteriaceae reveals phytohormones and antifungal metabolites · 2026 · DOI

• However, the construction and interactions of rare taxa within the soil‒plant continuum of medicinal plants and their impact on secondary metabolite accumulation remain poorly understood.

  Rare taxa as the major drivers of the secondary metabolite accumulation in Rheum tanguticum · 2025 · DOI

• Our research not only provided a novel myxobacterium species and a candidate enzyme for the development of new biocontrol agents but also reported an experimental basis for further study on different mechanisms of secreted predatory products in myxobacterial killing and degrading of Gram-negative and Gram-positive preys.

  Characteristics of a lipase ArEstA with lytic activity against drug-resistant pathogen from a novel myxobacterium, Archangium lipolyticum sp. nov. · 2024 · DOI

• This work sets the stage for further investigation of endophytic streptomycetes from Edelweiss aimed at the discovery and characterization of novel bioactive natural products.

  Genomes and secondary metabolomes of Streptomyces spp. isolated from Leontopodium nivale ssp. alpinum · 2024 · DOI

• Bacterial endophytes dwelling in medicinal plants represent an as yet underexplored source of bioactive natural products with the potential to be developed into drugs against various human diseases.

  Genomes and secondary metabolomes of Streptomyces spp. isolated from Leontopodium nivale ssp. alpinum · 2024 · DOI

• While there are approaches to activate and upregulate natural product biosynthesis in both native and heterologous microbial strains, a comprehensive strategy to elicit production of natural products as well as a generalizable and efficient method to interrogate diverse native strains collection, remains lacking.

  Exploring a general multi-pronged activation strategy for natural product discovery in Actinomycetes · 2024 · DOI

• Marine cyanobacteria represent a promising yet underexplored source of novel natural products with potent biological activities.

  Marine Cyanobacteria: A Rich Source of Structurally Unique Anti-Infectives for Drug Development · 2024 · DOI

• Accordingly, researchers have started exploring the understudied metabolites from endophytes as a new source of bioactive compounds.

  Bioprospecting Endophytic Fungi of Forest Plants for Bioactive Metabolites with Antibacterial, Antifungal, and Antioxidant Potentials · 2024 · DOI

• While non-heme iron 2-oxoglutarate dependent isonitrilases catalyze isonitrile formation, how the natural variation in INP structure is controlled and its implications for INP bioactivity remain open questions.

  Variation in Biosynthesis and Metal-Binding Properties of Isonitrile-Containing Peptides Produced by Mycobacteria versus Streptomyces · 2024 · DOI

• Currently, there are still plenty of intriguing hidden biosynthetic pathways of phenazine natural products to be discovered, and the titer of naturally occurring phenazine natural products is insufficient for agricultural applications.

  Recent Advances in Phenazine Natural Products: Biosynthesis and Metabolic Engineering · 2024 · DOI

• Although remarkable progress has been achieved in their chemistry and biosynthesis, the efflux of sorbicillinoids is poorly understood.

  MFS Transporter as the Molecular Switch Unlocking the Production of Cage-Like Acresorbicillinol C · 2024 · DOI

• Two compounds (8-octadecenoic acid methyl ester and 7,10-octadecadienoic acid methyl ester) were excluded due to logP values greater than 5, though they may still display biological activity or be optimized for non-oral delivery.

  Computational screening of GC-MS-derived secondary metabolites from Botryodiplodia theobromae (Lasiodiplodia theobromae) as potential ERBIN inhibitors in breast cancer · 2026 · DOI

• The need for new strategies to enhance antimicrobial compound production by Streptomyces sp. VITGV100. The potential of using chitosan nanoparticles as elicitors to improve the production of antimicrobial metabolites.

  Enhancing antimicrobial compound production in Streptomyces sp. VITGV100 using chitosan and its nanoparticles · 2026 · DOI

• The study identifies cholest-5-ene-16,22-dione as having high binding affinity to target protein 4URM through docking, but functional antimicrobial activity of this specific compound is not experimentally confirmed.

  Enhancing antimicrobial compound production in Streptomyces sp. VITGV100 using chitosan and its nanoparticles · 2026 · DOI

• The modification of piperazine alkaloids by DMATS remains unreported. There is a need to expand the chemical space of indole alkaloid derivatives.

  Discovery of unprecedented prenylated indole piperazines and pyrazines through cryptic biosynthetic gene cluster heterologous expression · 2026 · DOI

• The heterologous expression system was constructed in a single fungal host and evaluated only under static solid-state fermentation (CD-ST medium at 28°C for 7 days); expression in alternative fungal or bacterial hosts and evaluation under liquid culture conditions with varying aeration rates could enhance compound production.

  Discovery of unprecedented prenylated indole piperazines and pyrazines through cryptic biosynthetic gene cluster heterologous expression · 2026 · DOI

• Further investigation of the secondary metabolite biosynthesis potential of Streptomyces spp. from freshwater sediments. The development of new methods for metabolite profiling and identification. The exploration of the potential biotechnological applications of the novel compounds discovered.

  Unveiling the genomes and secondary metabolomes of Streptomyces spp. from freshwater sediments · 2026 · DOI

• The lack of investigation of Streptomyces spp. isolated from freshwater sediments. The need to explore new sources of secondary metabolites. The gap in knowledge about the secondary metabolite biosynthesis potential of Streptomyces spp. from freshwater sediments.

  Unveiling the genomes and secondary metabolomes of Streptomyces spp. from freshwater sediments · 2026 · DOI

• The traditional approach of selecting resistant mutants can be accompanied by undesired genomic alterations. There is a need for a novel approach to enhancing secondary metabolite production in Streptomyces.

  Rational construction of rpsL or/and rpoB merodiploids affects biosynthesis of secondary metabolite in Streptomyces · 2026 · DOI

• Further studies on the structure activity relationship of cyclic depsipeptides - Investigation of the potential of cyclic depsipeptides as privileged scaffolds for probing bacterial cell envelope organization and essential biosynthetic pathways - Development of new antibacterial agents based on cyclic depsipeptides

  Linking molecular architecture to antibacterial functions: a chemical biology view of cyclic depsipeptides · 2026 · DOI

• The need for developing new antibacterial agents that operate through novel mechanisms of action - The limited innovation in small molecule antibiotics - The escalating prevalence of resistant bacterial strains

  Linking molecular architecture to antibacterial functions: a chemical biology view of cyclic depsipeptides · 2026 · DOI

• The increasing resistance of bacteria to existing drugs. The need for new and effective antibacterial compounds. The challenge of isolating and characterizing new compounds from complex natural product extracts.

  Four new Cyclohexenone with antibacterial activity from the coral-derived fungus Aspergillus flavus · 2026 · 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
• antiSMASH 7.0: new and improved predictions for detection, regulation, chemical structures and visualisation · Nucleic Acids Research · 2023 · 2,348 citations
• THE MECHANISM OF ACTION OF FOSFOMYCIN (PHOSPHONOMYCIN) · Annals of the New York Academy of Sciences · 1974 · 652 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
• Chemical Evolution of Natural Product Structure · Journal of the American Chemical Society · 2022 · 212 citations
• MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration · Nucleic Acids Research · 2024 · 207 citations
• Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes · Drug Metabolism Reviews · 2002 · 204 citations
• Endophytic Fungi: An Effective Alternative Source of Plant-Derived Bioactive Compounds for Pharmacological Studies · Journal of Fungi · 2022 · 201 citations
• Characterization and heterologous reconstitution of Taxus biosynthetic enzymes leading to baccatin III · Science · 2024 · 194 citations

Most recent work

• Discovery and Biosynthesis of Nitrilobacillins by Post-translational Introduction of C-Terminal Nitrile Groups · bioRxiv · 2026
• Genome-guided discovery of tropansamycins: antimicrobial pentaketide ansamycins · Engineering Microbiology · 2026
• Atypical Condensation Domains Guide Discovery and Illuminate Biosynthesis of Myxoglucamides Featuring Vinyl‐Substituted, α‐Oxidized γ‐Amino Acids · Angewandte Chemie International Edition · 2026
• Construction of a library of gene expression elements in industrial Streptomyces and its application · Synthetic and Systems Biotechnology · 2026
• Amazonian Fungal Diversity and the Potential of Basidiomycetes as Sources of Novel Antimicrobials · Biology · 2026
• A comprehensive review of indole hybrids as anti-bacterial and anti-fungal agents: synthetic protocols and SAR studies · Future Medicinal Chemistry · 2026
• Title: DAP-Seq Reveals Cluster-Situated Regulator Control of Numerous Streptomyces Natural Product Biosynthetic Genes · Journal of Natural Products · 2026
• Genome Mining-Guided Discovery of the Glycosylated Griseorhodin Congener Ruskamycin · Journal of Natural Products · 2026
• Total synthesis of the proposed menominin A and its stereoisomers: identification of a highly potent isomer (1a) against RM-1 prostate cancer cells · Molecular Diversity · 2026
• Dfpenicimeroterpenoid A, Meroterpenoids with 6/6/6/4/5 Polycyclic Skeletons from the Marine-Derived Fungus Penicillium sp. DF71 · Organic Letters · 2026

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