Expanding the Chemical Diversity of Fasamycin Via Genome Mining and Biocatalysis

Abstract

Genome mining and biocatalytic modification of chemical structures are critical methods to develop new antibiotics. In this study, eight new fasamycins (3, 4, 6, and 8−12) along with five known analogues (1, 2, 5, 7, and 13) were obtained by the overexpression of two phosphopantetheinyl transferases (PPtases) in Streptomyces kanamyceticus and biocatalytic transformation with two halogenases. These new compounds displayed significant activity against Staphylococcus aureus and Bacillus subtilis, in particular, C-29-methyl and C-2/C-22-halogen derivatives. This study increases the chemical diversity of bioactive fasamycin derivatives and provides useful halogenation tools for engineering their scaffolds.

A deep learning model for type II polyketide natural product prediction without sequence alignment

“…5 and S6 †), whereas fasamycin from S. kanamyciticus was not detected under laboratory conditions as described in a recent study. 46…”

Anti-MRSA Dimeric and Brominated Phenyltetracenoids Produced by Streptomyces morookaense SC1169

“…Phenyltetracenoid polyketides, including fasamycins and congeners, are secondary metabolites produced by some Streptomyces strains. − They are attractive due to their potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). − ,− In order to discover compounds with better activity, genome mining, ,,,,,, biocatalytic modification, and the one-strain-many-compound (OSMAC) approaches ,,, have been applied to expand the chemical diversity of metabolites of this class. To date, more than 120 phenyltetracenoids have been reported.…”

“…To date, more than 120 phenyltetracenoids have been reported. While a majority of them bear chlorine substituents, a dozen of them are brominated derivatives, such as formicamycin K–M, formicapyridine G–I, naphthacemycin B 8 , and fasamycin S–V, X, and Y . The brominated metabolites were obtained from the sodium bromide (NaBr)-supplemented cultures of producing strains or in vitro enzymatic reactions, and some of them showed better antibacterial activity than their chlorinated counterparts. , …”

“…Compounds 6 and 8−11 were fasamycin-type metabolites with structures varied in number and positions of the O-methyl (C-13, C-15, and/or C-23) and with or without bromine substituents at C-14 and/or C-22, which were elucidated by analysis of their 1D NMR (Tables 3 and 4), 2D NMR (Figure S1, Supporting Information), and HRESIMS data. The known compounds, fasamycins R and S (12 and 13) 15 and accramycins A (14) 6 and B (15), 8 were characterized by comparing their spectroscopic data with literature data.…”

“…While a majority of them bear chlorine substituents, a dozen of them are brominated derivatives, such as formicamycin K−M, 4 formicapyridine G−I, 5 naphthacemycin B 8 , 14 and fasamycin S−V, X, and Y. 15 The brominated metabolites were obtained from the sodium bromide (NaBr)-supplemented cultures of producing strains or in vitro enzymatic reactions, and some of them showed better antibacterial activity than their chlorinated counterparts. 4,15 We recently reported 23 phenyltetracenoids produced by the soil-derived Streptomyces morookaense SC1169 cultivated on wheat and rice grains 7,11 and found that the chlorination at C-2 in fasamycin-type compounds displayed improved antibacterial activity and selectivity, including against MRSA and VRE.…”