Abstract
Rhamnolipids are a specific class of microbial surfactants, which hold great biotechnological and therapeutic potential. However, their exploitation at the industrial level is hampered because they are mainly produced by the opportunistic pathogen Pseudomonas aeruginosa. The non-human pathogenic bacterium Pantoea ananatis is an alternative producer of rhamnolipid-like metabolites containing glucose instead of rhamnose residues. Herein, we present the isolation, structural characterization, and total synthesis of ananatoside A, a 15-membered macrodilactone-containing glucolipid, and ananatoside B, its open-chain congener, from organic extracts of P. ananatis. Ananatoside A was synthesized through three alternative pathways involving either an intramolecular glycosylation, a chemical macrolactonization or a direct enzymatic transformation from ananatoside B. A series of diasteroisomerically pure (1→2), (1→3), and (1→4)-macrolactonized rhamnolipids were also synthesized through intramolecular glycosylation and their anomeric configurations as well as ring conformations were solved using molecular modeling in tandem with NMR studies. We show that ananatoside B is a more potent surfactant than its macrolide counterpart. We present evidence that macrolactonization of rhamnolipids enhances their cytotoxic and hemolytic potential, pointing towards a mechanism involving the formation of pores into the lipidic cell membrane. Lastly, we demonstrate that ananatoside A and ananatoside B as well as synthetic macrolactonized rhamnolipids can be perceived by the plant immune system, and that this sensing is more pronounced for a macrolide featuring a rhamnose moiety in its native 1C4 conformation. Altogether our results suggest that macrolactonization of glycolipids can dramatically interfere with their surfactant properties and biological activity.
Highlights
Bacteria represent a rich reservoir of structurally diverse glycosylated metabolites.2 Among these compounds, microbial glycolipids show considerable potential for biomedical and biotechnological applications.3 Microbial glycolipids are surfactants, i.e., amphiphilic surface-active compounds, whichRhamnolipids are a speci c class of microbial biosurfactants that have been intensively investigated in recent years.11 Structurally, rhamnolipids are a-con gured mono- or di-L-rhamnose residue(s) O-linked to an (R)-b-hydroxyalkanoic acid dilipidic chain of C6 to C14 carbon length
We demonstrate that ananatoside A and ananatoside B as well as synthetic macrolactonized rhamnolipids can be perceived by the plant immune system, and that this sensing is more pronounced for a macrolide featuring a rhamnose moiety in its native 1C4 conformation
The non-pathogenic bacterium P. ananatis BRT175 was found to be a producer of surface-active glycolipids based on its genetic homologies with rhamnolipid biosynthetic genes
Summary
As part of our research program on the synthesis of microbial glycans, we are interested in developing synthetic routes that would allow an alternative and straightforward access to these macrodilactone-containing glycolipids, and enable the assessment of their tensioactive properties and biological activities Within this framework, we present the total synthesis of ananatoside A [1], its newly identi ed open-chain congener ananatoside B [2], the related RhaC10C10 [3] as well as ve unprecedented, anomerically pure (1/2)-, (1/3)-, and (1/4)-macrodilactone-containing rhamnolipids [4,5,6] (Fig. 1). DFT calculations were used to decipher the ring conformations and anomeric con gurations of synthetic macrolactonized rhamnolipids 4–6, which were readily obtained through intramolecular glycosylation Their surfactant properties and biological activity, i.e., antimicrobial activity, cytotoxicity, hemolytic activity, as well as their interaction with the plant immune system, were investigated, providing meaningful fundamental insights into the impact of the presence of the macrodilactonic ring on the physical and biological properties of this relevant class of microbial glycolipids
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