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

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 approach where simpler and fully synthetic intermediates of the natural product’s biosynthesis can be biotechnologically incorporated. Here, we report the synthesis of a series of tripeptide thioesters as mutasynthons containing the native sequence with a dehydroalanine (Dha) Michael acceptor attached to a sarcosine (Sar) and derivatives. Chemical synthesis of the native sequence ᴅ-Ala-Dha-Sar thioester required revision of the sequential peptide synthesis into a convergent strategy where the thioester with sarcosine was formed before coupling to the Dha-containing dipeptide.

Active substances of myxobacteria against plant diseases and their action mechanisms

“…Several derivatives of argyrin A could be obtained by modifying the methoxytry ptophan residue. The methoxy group of this residue was crucial for its antibacterial activity and its activity will be lost if the position is replaced by other substituents ( Siebert et al, 2019 ). Argyrin has antibacterial activity against bacteria, so there is great practical value to study its antibacterial activity against plant pathogenic bacteria.…”

Corrigendum: Active substances of myxobacteria against plant diseases and their action mechanisms

“…Among them, protocystin A combines with elongation factor G (EF-G) as its target. Several derivatives of protocystin A can be obtained by modifying the methoxytryptophan residue, and the methoxy group is located the antibacterial activity will be lost if the position is replaced by other substituents (Siebert et al, 2019 ). ]” The corrected sentence appears below: “[The culture medium of the strains of Archangium gephyra contained a group of cyclic peptides composed of naturally produced octapeptides, which exhibited strong antibiotic effects against P. aeruginosa (Nickeleit et al, 2008 ; Stauch et al, 2010 ; Wieland et al, 2022 ).…”

“…Several derivatives of argyrin A could be obtained by modifying the methoxytry ptophan residue. The methoxy group of this residue was crucial for its antibacterial activity and its activity will be lost if the position is replaced by other substituents (Siebert et al, 2019 ). Argyrin has antibacterial activity against bacteria, so there is great practical value to study its antibacterial activity against plant pathogenic bacteria.…”

The cyclic octapeptide antibiotic argyrin B inhibits translation by trapping EF-G on the ribosome during translocation

“…Total chemical synthesis has been accomplished for ArgA, ArgB, ArgE, and ArgF ( 8 – 10 ), allowing research into modifications to improve tolerability, increase specificity, and monitor pharmacokinetics ( 11 – 13 ), thereby making the argyrins an attractive family of compounds for further antibiotic development. Additionally, argyrins display promising activity against Pseudomonas aeruginosa ( 3 , 14 – 17 ), with ArgB at the forefront ( 4 ).…”