Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• Saarbrücken, Germany 10.3762/bjoc.15.286 Abstract The argyrins are secondary metabolites from myxobacteria with antibiotic activity against Pseudomonas aeruginosa. Studying their structure–activity relationship is hampered by the complexity of the chemical total synthesis. Mutasynthesis is a promising

• ; mutasynthesis; NRPS; peptide synthesis; Introduction Resistance to antibiotics is currently a major threat to public health. Especially Gram-negative bacterial pathogens are of concern, due to their widespread development of resistance mechanisms. To address this general antimicrobial resistance problem, new

• has been observed in many cases that exogenous substrates can be incorporated by bacteria into biosynthesis cascades of natural products. The use of substrates which lead to nonnatural derivatives of the natural product coined the field of mutasynthesis, e.g., siderophore analogue biosynthesis by P

A non-canonical peptide synthetase adenylates 3-methyl-2-oxovaleric acid for auriculamide biosynthesis

• Daniel Braga,
• Dirk Hoffmeister and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 2766–2770, doi:10.3762/bjoc.12.274

• enzymatic activity, molecules with methylene α-carbons led to low turnover. Such enzymatic plasticity is an important attribute to help in the perpetual search for novel molecules and to access a greater structural diversity by mutasynthesis. Keywords: adenylation; auriculamide; biosynthesis; Herpetosiphon

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• analyzed in vivo in a mutasynthesis study employing a Myxococcus fulvus mutant unable to biosynthesize the western chain. This study revealed that MxnB is capable of condensing a wide variety of activated synthetic western chains with the carrier protein bound native eastern chain [90]. The two proposed

A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis

• Darko Kresovic,
• Florence Schempp,
• Zakaria Cheikh-Ali and
• Helge B. Bode

Beilstein J. Org. Chem. 2015, 11, 1412–1417, doi:10.3762/bjoc.11.152

• products have been shown to be potent antibiotics targeting the newly identified switch region of the bacterial RNA polymerase [24]. Furthermore the promiscuity of MxnB regarding its substrate specificity has been used in mutasynthesis experiments to produce novel myxopyronin derivatives [25]. Recently the

• , Supporting Information File 1) similar to that of photopyrone (Scheme 1). Interestingly, PpyS and PyrS differ in substrate specificity for the acyl substrates. With this knowledge, it might now be possible to perform mutasynthesis experiments for the production of new, more potent compounds. It could also be

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• ; antitumor agents; click chemistry; mutasynthesis; natural products; Introduction Although natural products and analogues cover a large portion of the drug market particularly in the treatment of cancer as well as bacterial and viral infections their role in pharmaceutical research has decreased over the

• applications [4]. In this context, producer strains that are genetically engineered in the biosynthesis of important and complex natural products have shown to be powerful synthetic tools, e.g., knock out mutants are key players in mutational biosynthesis, or in short mutasynthesis. This technique relies on

• , we demonstrated that the ansamitocins (maytansinoids) 3–5 are an ideal showcase for creating small libraries by mutasynthesis [8][9][10]. These secondary metabolites exert strong antiproliferative activity towards different leukemia cell lines as well as human solid tumors. Inhibitory concentrations

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• promiscuity of wild type MatB malonyl-CoA synthetases was recently described [40], pointing out the need for an artificial and versatile activation mechanism as described here, to enable what we have termed enzyme-directed mutasynthesis. Conclusion Based on the single incorporation of 4 a relative

Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations

• Tobias Knobloch,
• Gerald Dräger,
• Wera Collisi,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2012, 8, 861–869, doi:10.3762/bjoc.8.96

• . Keywords: ansamitocins; antibiotics; antitumor agents; mutasynthesis; natural products; Introduction Natural products still play an important role as lead structures for the treatment of infectious diseases and cancer. However, natural products have lost some of their attraction for the development of

• ]. Producer strains genetically blocked in the biosynthesis of important and complex natural products can serve as such new tools. The synthetic concept based on these blocked mutants is termed “mutational biosynthesis”, or in short mutasynthesis, and it relies on the cellular uptake of modified biosynthetic

• intermediates, sometimes termed mutasynthons, and their incorporation into complex secondary metabolites [5][6][7]. When making use of mutants that are blocked in early stages of a given biosynthesis pathway, the concept of mutasynthesis may be compared to a (partial) natural product total synthesis. When

Biosynthesis and function of secondary metabolites

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2011, 7, 1620–1621, doi:10.3762/bjoc.7.190

• , e.g., of oxidation states of the natural product’s carbon backbone by simple domain knockouts within the responsible megasynthases, or the introduction of a variety of alternative biosynthetic starters by mutasynthesis approaches, thus leading to new variants of known metabolites, which may have