Total Synthesis, Isolation, Surfactant Properties, and Biological Evaluation of Ananatosides and Related Macrodilactone-Containing Rhamnolipids
2021
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 prove that macrolactonization of glycolipids can dramatically
interfere with their surfactant properties and biological activity.
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