Unexpected Biosynthesis of Fluorescein-Like Arthrocolins against Resistant Strains in an Engineered Escherichia coli

Abstract

Here we provide an unprecedented biofactory where fluorescent dye-like complex xanthenes could be produced in an engineered Escherichia coli. Feeding the strain with toluquinol or hydroquinones resulted in production of novel "unnatural" natural products including four arthrocolins embedded with indolyltriphenyl quaternary carbons. Arthrocolins A−C potently inhibited various human cancer cell lines including paclitaxel-resistant cell line A549/Taxol and methicillin-resistant Staphylococcus aureus and immensely restored the sensitivity of intractable fluconazole-resistant human pathogen Candida albicans to fluconazole.

9-Trifluoromethylxanthenediols: Synthesis and Supramolecular Motifs

“…A recent search in the Cambridge Crystallographic Data Centre, performed using ConQuest 2021.1.0 software, indicates that approximately 2350 related structures have been deposited, including 9-xanthones (Figure b), xanthene dyes (Figure c), or xantphos-related structures (Figure d). A xanthenediol structure can also be found in the recent work from Niu and collaborators (HORMUZ, Figure e) . Nevertheless, to this date, only one TFXdiol structure has been reported in detail so far (Figure f).…”

“…(b) Overlay of the crystallographic independent XTFdiols of the structures in this work. The related xanthenediol structure HORMUZ was included for a better comparison …”

“…A xanthenediol structure can also be found in the recent work from Niu and collaborators (HORMUZ, Figure 1 e). 31 Nevertheless, to this date, only one TFXdiol structure has been reported in detail so far ( Figure 1 f). The reported 3,6-dimethyl-9-phenyl-9-trifluoromethyl-9 H -xanthene-2,7-diol was used as an intermediate in the obtaining quinone-hydroquinone hybrid structures in stereodynamic redox reactions.…”

Arthrocolins Synergizing with Fluconazole Inhibit Fluconazole-Resistant Candida albicans by Increasing Riboflavin Metabolism and Causing Mitochondrial Dysfunction and Autophagy

“…In our continuing research on natural products with antifungal activities from microbes, we found that arthrocolins (Acs) A to C ( Fig. 1A ) obtained from Escherichia coli fed with a key precursor, toluquinol, that was widely distributed in many fungi, could immensely recover the antifungal activity of FLC against intractable FLC-resistant C. albicans ( 16 ). Different from artificially synthesized fluorescent xanthenes, Acs are a class of seminaturally occurring fluorescent dye-like xanthenes with an unprecedented carbon skeleton containing a rare indolyltriphenyl quaternary carbon.…”

Novel Polyketide-Terpenoid Hybrid Metabolites and Increased Fungal Nematocidal Ability by Disruption of Genes 277 and 279 in Nematode-Trapping Fungus Arthrobotrys oligospora

“…Interestingly, PK-TP hybrid farnesyltoluquinol ( 1 ) has long been assumed as the fourth key precursor or the first PK-TP hybrid precursor in the biosynthetic pathway for SEC metabolites. − However, further heterologous expression of prenyltransferase gene 276 from A. oligospora in Escherichia coli and then in vitro biochemical experiment combined with HPLC-MS analysis suggested the presence of another PK-TP hybrid compound prenyltoluquinol ( 2 ) instead of farnesyltoluquinol ( 1 ), indicating that prenyltransferase 276 might be only involved in prenylation of toluquinol, instead of farnesylation of toluquinol as previously proposed . This allowed us to suggest that prenyltoluquinol ( 2 ) should undergo further prenylation to yield farnesyltoluquinone ( 1 ).…”