Marine Bacterial Aromatic Polyketides From Host-Dependent Heterologous Expression and Fungal Mode of Cyclization

Abstract

The structure diversity of type II polyketide synthases-derived bacterial aromatic polyketides is often enhanced by enzyme controlled or spontaneous cyclizations. Here we report the discovery of bacterial aromatic polyketides generated from 5 different cyclization modes and pathway crosstalk between the host and the heterologous fluostatin biosynthetic gene cluster derived from a marine bacterium. The discovery of new compound SEK43F (2) represents an unusual carbon skeleton resulting from a pathway crosstalk, in which a pyrrole-like moiety derived from the host Streptomyces albus J1074 is fused to an aromatic polyketide SEK43 generated from the heterologous fluostatin type II PKSs. The occurrence of a new congener, fluoquinone (3), highlights a bacterial aromatic polyketide that is exceptionally derived from a characteristic fungal F-mode first-ring cyclization. This study expands our knowledge on the power of bacterial type II PKSs in diversifying aromatic polyketides.

Marine Pyrrole Alkaloids

“…Among the huge variety of marine alkaloids, aromatic polyketides (APK) represent another large class of MNPs and pyrrole-containing representatives have been described. The group of Zhang and co-workers isolated the decaketide pyrrole SEK43F ( 75 ) generated from pathway crosstalk of the host Streptomyces albus J1074 and the heterologous fls-gene cluster from Micromonospora rosaria SCSIO N160 ( Figure 10 ) [ 91 ]. It should be mentioned that the configuration of the double bond in 75 could not be unequivocally determined.…”

“…It should be mentioned that the configuration of the double bond in 75 could not be unequivocally determined. The same group also isolated another tri-methylated bis-pyrrole 76 ( Figure 10 ) [ 91 ], which has only been known as a synthetic product before [ 92 , 93 ]. Both compounds 75 and 76 displayed negligible antibacterial activity, whereas the APK 75 showed weak to moderate cytotoxicity against four human cancer cell lines (SF-268, MCF-7, NCI-H460, and HePG-2, with IC 50 values of 56.46 µM ± 0.87 µM, 35.73 µM ± 1.45 µM, 44.62 µM ± 2.49 µM, and 39.22 µM ± 3.00 µM, respectively, Figure 10 ).…”

Targeted Genome Mining—From Compound Discovery to Biosynthetic Pathway Elucidation

“…Thus, it is obvious that SEK90 as well as SEK87 derives from the combination of an unbalanced performance of pentangumycins minimal PKS, which seems to be uncoordinated with the activity of the Pen cyclases, leading to accumulation of SEK43 and the primary metabolism of S. lividans . A similar situation was proposed for the assembly of SEK43F, which resulted from interplay between the primary metabolism of the host strain S. albus and the heterologously expressed fluostatins type II PKS gene cluster [ 70 ].…”

“…Tü6384 [ 69 ]. On the other hand, its derivative, named SEK43F, resulting from fusion of SEK43 with the pyrole-like moiety, was isolated from the recombinant S. albus expressing fluostatin biosynthetic gene cluster [ 70 ]. Nevertheless, a dimerization of this compound has not been described thus far.…”

Discovery of Stealthin Derivatives and Implication of the Amidotransferase FlsN3 in the Biosynthesis of Nitrogen-Containing Fluostatins

“…A growing number of benzofluorene-containing atypical angucycline type of aromatic polyketides have been discovered to exhibit significant antibacterial and antitumor activities [1,2], including kinamycins [3], lomaiviticins [4,5,6], nenestatins [7], and fluostatins [8,9,10,11,12,13]. The diazo groups in lomaiviticin A have been reported to play an indispensable role in the potent cytotoxicity against a panel of human cancer cell lines by inducing double-strand breaks in DNA via the formation of vinyl radical intermediate [4,6].…”