Combinatorial biosynthesis yields novel hybrid argimycin P alkaloids with diverse scaffolds in Streptomyces argillaceus

Abstract

Coelimycin P1 and argimycins P are two types of polyketide alkaloids produced by Streptomyces coelicolor and Streptomyces argillaceus, respectively. Their biosynthesis pathways share some early steps that render very similar aminated polyketide chains, diverging the pathways afterwards. By F I G U R E 2 Analysis of PKS modules and biosynthesis steps of coelimycin P1 and argimycins P. (A) coelimycin P1, (B) argimycins P and (C) proposed biosynthesis of hybrid argimycin compounds. ARP, argimycins P; CPK, coelimycin P1.

Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome

“…Moreover, by overexpressing three genes (ahbH, ahbI, and ahbL2) for the synthesis and activation of 3,4-AHBA, a new hybrid compound, AHB18, was identified, containing a 3,4-AHBA moiety and an ARP bicyclic derivative constituted by a 2,3-dihydropiridine ring fused with a five-membered ring. This ARP moiety closely resembles those synthesized during the final steps of the ARP biosynthetic pathway [17,25,26]. Biosynthesis of AHB18 would result from a metabolic crosstalk between the AHB and the ARP pathways.…”

“…Although the reported AHBs did not show antibiotic activity (except AHB75), the identification of the ahb genes opens the possibility to use those genes as tools to generate potentially new bioactive compounds by combinatorial biosynthesis. In this sense, we have recently reported a new hybrid antibiotic compound generated by combining genes from the arp and cpk clusters, which encode the non-bioactive compounds ARP and coelimycin P, respectively [26].…”

“…The major compound 1 detected in n-butanol extracts at 360 nm was purified from cultures of S. argillaceus (pEM4T-AHBA) grown in R5A, and structurally characterized (see below). It corresponded to a hybrid new compound constituted by two moieties, a 3,4-AHBA and an ARP compound [17,25,26], and it was given the name ahbamycin 18 (AHBA18) (Figure 4).…”

“…The major compound 1 detected in n-butanol extracts at 360 nm was purified from cultures of S. argillaceus (pEM4T-AHBA) grown in R5A, and structurally characterized (see below). It corresponded to a hybrid new compound constituted by two moieties, a 3,4-AHBA and an ARP compound [17,25,26], and it was given the name ahbamycin 18 (AHBA18) (Figure 4). The third approach was overexpression of regulatory genes from the ahb cluster dividual overexpression of ahbR2 and ahbR3 that encode AfsR/SARP putative trans tional activators did not result in production of any differential compound.…”