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Discovery and development of diterpene-based inhibitors of ArnT-mediated colistin resistance

Andrea Calcaterra

Colistin is a last-line antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural ent-beyerene diterpene was identified as a promising inhibitor of the enzyme responsible for colistin resistance mediated by lipid A aminoarabinosylation in Gram-negative bacteria, namely ArnT (undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase). To explore the structure-activity relationship (SAR), semi-synthetic analogs of hit were designed, synthesized, and tested against colistin-resistant Pseudomonas aeruginosa strains, including clinical isolates. Microbiological assays coupled with molecular modeling showed that the ent-beyerane scaffold bearing an oxalate group at C18/C-19, or a sugar moiety at C-19 to resemble L-Ara4N is a fundamental requirement for a more efficient inhibition of bacterial growth likely resulting from a more efficient inhibition of ArnT activity. The easy accessibility of ent-beyerane scaffold from Stevia rebaudiana secondary metabolites provided an effective tool for the development of promising colistin resistance inhibitors.