DEVELOPMENT OF ArnT-MEDIATED COLISTIN RESISTANCE DITERPENE-BASED INHIBITORS

Colistin is a last-line antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections.1 Recently, a natural ent-beyerene diterpene (ent-Beyer-15-en-18-O-oxalate) 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).2 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 (figure 1), in order to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling demonstrated that an ent-beyerane scaffold bearing an oxalate like group at C-18/C-19, or a sugar residue at C-19 to resemble L-Ara4N is an essential requirement for a more efficient inhibition of bacterial growth likely resulting from a more efficient inhibition of ArnT activity. Importantly, the easy accessibility of ent-beyerane scaffold from Stevia rebaudiana secondary metabolites will provide a cost-effective key platform for the development of promising colistin resistance inhibitors.