Bonsecamin: A New Cyclic Pentapeptide Discovered through Heterologous Expression of a Cryptic Gene Cluster

Lasch, Constanze; Stierhof, Marc; Estévez, Marta Rodríguez; Myronovskyi, Maksym; Zapp, Josef; Luzhetskyy, Andriy

doi:10.3390/microorganisms9081640

Cited by 6 publications

(12 citation statements)

References 36 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For the studies reviewed here, the rationale for BGC selection was based either on a) predicted structural novelty, b) biosynthetic class, c) structure similarity to known antibiotic class or d) biological activity of library clone (Figure 2A). The most frequent approach (56%) was to prioritize novelty by expressing unusual BGCs found in rare and/or understudied bacteria, exemplified by the discovery of the lanthipeptide marinsedin from Marinicella sedimis (Han et al 2022), and by the discovery of 31 other compounds listed in SI Table S1 (Hashimoto et al 2021;Hao et al 2019;Zhang et al 2021;Lasch et al 2021;Enghiad et al 2021;Shi et al 2019;Yuet et al 2020;De Rond, Asay, and Moore 2021;Wang et al 2023;Liu et al 2021;Lasch, Stierhof, et al 2020;Li et al 2020;Myronovskyi et al 2018;Gao et al 2023;Cheng et al 2023;Koos and Link 2019;Kaweewan, Nakagawa, and Kodani 2021;S. H. Liu et al 2019;Shuai et al 2020;Lasch, Gummerlich, et al 2020;Paulus et al 2022;Bothwell et al 2021;Gummerlich et al 2020;Alberti et al 2019;Vermeulen et al 2022;Zhang et al 2021;Unno et al 2020).…”

Section: Bgc Prioritization Biosynthetic Class and Host Taxamentioning

confidence: 99%

Bacterial natural product discovery by heterologous expression

Kadjo,

Eustaquio

2023

Preprint

View full text Add to dashboard Cite

Natural products have found important applications in the pharmaceutical and agricultural sectors. In bacteria, the genes that encode the biosynthesis of natural products are often colocalized in the genome, forming biosynthetic gene clusters. It has been predicted that only 3% of natural products encoded in bacterial genomes have been discovered thus far, in part because gene clusters may be poorly expressed under laboratory conditions. Heterologous expression can help realize bioinformatics predictions into products. However, challenges remain such as gene cluster prioritization, cloning of the complete gene cluster, appropriate expression, product identification, and isolation of products in practical yields. Here we reviewed the literature from the past five years (January 2018 to June 2023) to identify studies that discovered natural products by heterologous expression. From the 50 studies identified, we present analyses of the rationale for gene cluster prioritization, cloning methods, biosynthetic class, source taxa, and host choice. Combined, the 50 studies led to the discovery of 63 new families of natural products, supporting heterologous expression as a promising way to access novel chemistry. However, the success rate of natural product detection varied from 11% to 32% based on four large-scale studies that were identified. The low success rate makes it apparent that much remains to be improved. The potential reasons for failure and points to be considered to improve the chances of success are discussed.

show abstract

Section: Bgc Prioritization Biosynthetic Class and Host Taxamentioning

confidence: 99%

Bacterial natural product discovery by heterologous expression

Kadjo,

Eustaquio

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…These developments led to the discovery of cryptic biosynthetic gene clusters (BGCs) in Streptomyces coelicolor two decades ago and revealed an abundance of new natural products hidden in the genomes of streptomycetes . Previous work has shown that activation of cryptic BGCs by heterologous expression in optimized host strains such as Streptomyces lividans Δ8 and Streptomyces albus Δ14 is a powerful tool to unlock this potential. − In this work, genome mining, heterologous expression, and dereplication were used to identify new natural product scaffolds from the less studied strain Streptomyces aureus LU18118. This led to the discovery of new threonine-16:0dioic acids named lipothrenins and the corresponding BGC, named lit -cluster.…”

mentioning

confidence: 99%

Heterologous Production and Biosynthesis of Threonine-16:0dioic acids with a Hydroxamate Moiety

Stierhof,

Myronovskyi,

Zapp

et al. 2023

J. Nat. Prod.

Self Cite

View full text Add to dashboard Cite

Dereplication and genome mining in Streptomyces aureus LU18118 combined with heterologous expression of selected biosynthetic gene clusters (BGCs) led to the discovery of various threonine-16:0dioic acids named lipothrenins. Lipothrenins consist of the core elements L-Thr, D-allo-Thr, or Dhb, which are linked to hexadecanedioic acid by an amide bond. The main compound lipothrenin A (1) carries the N-hydroxylated Dallo form of threonine and expresses a siderophore activity. The lipothrenin BGC was analyzed by a series of deletion experiments. As a result, a variety of interesting genes involved in the recruitment and selective activation of linear 16:0dioic acids, amide bond formation, and the epimerization of L-Thr were revealed. Furthermore, a diiron N-oxygenase was identified that may be directly involved in the monooxygenation of the amide bond. This is divergent from the usual hydroxamate formation mechanism in siderophores, which involves hydroxylation of the free amine prior to amide bond formation. Siderophore activity was observed for all N-hydroxylated lipothrenins by application of the CAS assay method.

show abstract

“…Bacteria and fungi produce many of these compounds as a courtesy of nonribosomal biosynthetic enzymatic pathways, which involve multimodular megaenzymes named nonribosomal peptide synthetases (NRPSs). This Special Issue includes a review highlighting recent progress in understanding the complexity of the mechanisms of nonribosomal synthesis [ 1 ], and five research articles describing the successful discovery of new nonribosomal peptides [ 2 , 3 , 4 , 5 ], their structural characterization [ 3 , 5 ], and their relationship with the taxonomic position of the producing strains [ 6 ].…”

mentioning

confidence: 99%

“…Interestingly, four out the five research articles describe nonribosomal peptide synthesis mechanisms that mainly work out of the canonical rules. The in silico analysis of nonribosomal BGCs, together with heterologous expression, represents a successful strategy that resulted in the discovery of BE-18257 antibiotics and pentaminomycins [ 2 ], cyclic depsibosamycins [ 3 ], and bonsecamin [ 4 ].…”

mentioning

confidence: 99%