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Many clinically used drugs are derived from or inspired by bacterial natural products that often are produced through nonribosomal peptide synthetases (NRPSs), megasynthetases that activate and join individual amino acids in an assembly line fashion. In this work, we describe a detailed phylogenetic analysis of several bacterial NRPSs that led to t...
The human microbiome has emerged as a rich source of diverse and bioactive natural products, harboring immense potential for therapeutic applications. To facilitate systematic exploration and analysis of its biosynthetic landscape, we present ABC-HuMi: the Atlas of Biosynthetic Gene Clusters (BGCs) in the Human Microbiome. ABC-HuMi integrates data...
Reprogramming biosynthetic assembly-lines is a topic of intense interest. This is unsurprising as the scaffolds of most antibiotics in current clinical use are produced by such pathways. The modular nature of assembly-lines provides a direct relationship between the sequence of enzymatic domains and the chemical structure of the product, but ration...
Re-engineering of non-ribosomal peptide synthetases (NRPSs) is challenging due to their protein size up to a few megadalton. The artificial splitting of NRPSs to produce building blocks with moderate size is achieved by the introduction of synthetic zippers, which can be recombined in a rapid and simple plug and play manner to form an in trans regu...
Peptides derived from non-ribosomal peptide synthetases (NRPSs) represent an important class of pharmaceutically relevant drugs. Methods to generate novel non-ribosomal peptides or to modify peptide natural products in an easy and predictable way are therefore of great interest. However, although the overall modular structure of NRPSs suggests the...
The eXchange Unit between Thiolation domains approach and artificial intelligence (AI)‐driven tools like Synthetic Intelligence are transforming nonribosomal peptide synthetase and polyketide synthase engineering, enabling the creation of novel bioactive compounds that address critical challenges like antibiotic resistance and cancer. These innovat...
Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To sh...
The human microbiome emerges as a promising reservoir for diagnostic markers and therapeutics. Since host-associated microbiomes at various body sites differ and diseases do not occur in isolation, a comprehensive analysis strategy highlighting the full potential of microbiomes should include diverse specimen types and various diseases. To ensure r...
The recently identified natural product NOSO‐95A from entomopathogenic Xenorhabdus bacteria, derived from a biosynthetic gene cluster (BGC) encoding a non‐ribosomal peptide synthetase (NRPS), was the first member of the odilorhabdin class of antibiotics. This class exhibits broad‐spectrum antibiotic activity and inspired the development of the synt...
The recently identified natural product NOSO‐95A from entomopathogenic Xenorhabdus bacteria, derived from a biosynthetic gene cluster (BGC) encoding a non‐ribosomal peptide synthetase (NRPS), was the first member of the odilorhabdin class of antibiotics. This class exhibits broad‐spectrum antibiotic activity and inspired the development of the synt...
Bacterial biosynthetic assembly lines, such as nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), play a crucial role in the synthesis of natural products that have significant therapeutic potential. The ability to engineer these biosynthetic assembly lines offers opportunities to produce artificial nonribosomal peptides, pol...
The bioengineering of nonribosomal peptide synthetases (NRPSs) is a rapidly developing field to access natural product derivatives and new-to-nature natural products like scaffolds with changed or improved properties. However, the rational (re-)design of these often gigantic assembly-line proteins is by no means trivial and needs in-depth insights...
Bacterial biosynthetic assembly lines, such as non-ribosomal peptide synthetases (NRPS) and polyketide synthases, are often subject of synthetic biology-because they produce a variety of natural products invaluable for modern pharmacotherapy. Acquiring the ability to engineer these biosynthetic assembly lines allows the production of artificial non...
24 Many clinically used drugs are derived from or inspired by bacterial natural products 25 that often are biosynthesised via non-ribosomal peptide synthetases (NRPS), giant 26 megasynthases that activate and join individual amino acids in an assembly line 27 fashion. Since NRPS are not limited to the incorporation of the 20 proteinogenic amino 28...
Several clinically used drugs are derived from microorganisms that often produce them via non-ribosomal peptide synthetases (NRPS), giant megasynthases that activate and connect individual amino acids in an assembly line fashion. Since NRPS are not restricted to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation wou...
Benzoxazolinate is a rare bis‐heterocyclic moiety that interacts with proteins and DNA and confers extraordinary bioactivities on natural products, such as C‐1027. However, the biosynthetic gene responsible for the key cyclization step of benzoxazolinate remains unclear. Herein, we show a putative acyl AMP‐ligase responsible for the last cyclizatio...
Benzoxazolinate is a rare bis‐heterocyclic moiety that interacts with proteins and DNA and confers extraordinary bioactivities on natural products, such as C‐1027. However, the biosynthetic gene responsible for the key cyclization step of benzoxazolinate remains unclear. Here, we show a putative acyl AMP‐ligase responsible for the last cyclization...
A rich source of new therapeutics are natural products derived from modular non-ribosomal peptide synthetases (e. g. penicillins, daptomycin). Yet, efficient bioengineering of these often gigantic megaenzymes to generate natural product analogs is a major challenge. Using synthetic zippers, we have established a co-expression strategy that not only...
Bacterial natural products in general, and non‐ribosomally synthesized peptides in particular, are structurally diverse and provide us with a broad range of pharmaceutically relevant bioactivities. Yet, traditional natural product research suffers from rediscovering the same scaffolds and has been stigmatized as inefficient, time‐, labour‐ and cost...
Streptomyces clavuligerus is an industrially important actinomycete whose genetic manipulation is limited by low transformation and conjugation efficiencies, low levels of recombination of introduced DNA, and difficulty in obtaining consistent sporulation. We describe the construction and application of versatile vectors for Cas9-mediated genome ed...
Bacterial natural products in general, and non-ribosomally synthesized peptides in particular, are structurally diverse and provide us with a broad range of pharmaceutically relevant bioactivities. Yet, traditional natural product research suffers from rediscovering the same scaffolds and has been stigmatised as inefficient, time-, labour-, and cos...
Many clinically used natural products are produced by non-ribosomal peptide synthetases (NRPSs), which due to their modular nature should be accessible to modification and engineering approaches. While the adenylation domain (A) plays the key role in substrate recognition and activation, the condensation domain (C) which is responsible for substrat...
Non‐ribosomal peptide synthetases (NRPSs) are the origin of a wide range of natural products, including many clinically used drugs. Efficient engineering of these often giant biosynthetic machineries to produce novel non‐ribosomal peptides (NRPs) is an ongoing challenge. Here we describe a cloning and co‐expression strategy to functionally combine...
Reprogramming biosynthetic assembly-lines is a topic of intense interest. This is unsurprising as the scaffolds of most antibiotics in current clinical use are produced by such pathways. The modular nature of assembly-lines provides a direct relationship between the sequence of enzymatic domains and the chemical structure of the product, but ration...
Non-ribosomal peptide synthetases (NRPSs) are the origin of a wide range of natural products, including many clinically used drugs. Engineering of these often giant biosynthetic machineries to produce novel non-ribosomal peptides (NRPs) at high titre is an ongoing challenge. Here we describe a strategy to functionally combine NRPS fragments of Gram...
Numerous important therapeutic agents, including widely-used antibiotics, anti-cancer drugs, immunosuppressants, agrochemicals and other valuable compounds, are produced by microorganisms. Many of these are biosynthesised by modular enzymatic assembly line polyketide synthases, non-ribosomal peptide synthetases, and hybrids thereof. To alter the ba...
Non-ribosomal peptide synthetases (NRPSs) are giant enzyme machines that activate amino acids in an assembly line fashion. As NRPSs are not restricted to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would enable microbial production of a diverse range of peptides; however, the structural requirements for repro...
Many important natural products are produced by non-ribosomal peptide synthetases (NRPSs). These giant enzyme machines activate amino acids in an assembly line fashion in which a set of catalytically active domains is responsible for the section, activation, covalent binding and connection of a specific amino acid to the growing peptide chain. Sinc...
Although the first natural products (NP) from Photorhabdus and Xenorhabdus bacteria have been known now for almost 30 years, a huge variety of new compounds have been identified in the last 5–10 years, mainly due to the application of modern mass spectrometry. Additionally, application of molecular methods that allow the activation of NP production...
Six new lipodepsipeptides (I) and an additional linear derivative (II) named taxlllaids A-G are isolated and their structures are elucidated by spectroscopic methods, labeling and MS experiments.
Simple urea compounds ("phurealipids") have been identified from the entomopathogenic bacterium Photorhabdus luminescens, and their biosynthesis was elucidated. Very similar analogues of these compounds have been previously developed as inhibitors of juvenile hormone epoxide hydrolase (JHEH), a key enzyme in insect development and growth. Phurealip...
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Six new lipodepsipeptides and an additional linear derivative named taxlllaids A–G (1–7) have been identified in the entomopathogenic bacterium Xenorhabdus indica. The structures of the main compounds have been solved by detailed NMR spectroscopic analysis and the structures of minor derivatives were elucidated by a combination of labelling experim...
Fatty acid-derived ether lipids are present not only in most vertebrates but also in some bacteria. Here we describe what is to our knowledge the first gene cluster involved in the biosynthesis of such lipids in myxobacteria that encodes the multifunctional enzyme ElbD, which shows similarity to polyketide synthases. Initial characterization of elb...
Overlooked but widespread! A new class of ketosynthases (DarB) involved in the biosynthesis of 1,3-cyclohexanediones and dialkylresorcinols has been identified and characterized in detail. The presence of homologues in 89 different bacteria, including several pathogens, reveals that DarB as well as the corresponding natural products might be widesp...