Exploration of the aromatic abietane diterpenoid scaffold in the development of ArnT-mediated colistin resistance inhibitors

Abstract

Colistin is a last-resort antibiotic for treating multidrug-resistant Gram-negative bacterial infections. However, some bacteria, such as Pseudomonas aeruginosa, can develop resistance to colistin thanks to the modification of the lipid A component of the outer membrane catalyzed by the 4-amino-4-deoxy-L-arabinose transferase ArnT. Here, building on our previous identification of the natural ent-beyerene diterpene FDO as an ArnT inhibitor, we report a rational procedure to simplify the ent-beyerene scaffold into drug-like synthetic ArnT inhibitors. Starting from the aromatic abietane scaffold of podocarpic acid 1, a function-oriented synthesis (FOS) approach guided the preparation of twenty-four semisynthetic oxygen and nitrogen abietane-based derivatives. Biological evaluation against a colistin-resistant P. aeruginosa strain revealed that four compounds (2, 13, 18, and 30) significantly restore the activity of sub-inhibitory colistin, with compound 18 showing the lowest IC₉₀ (182.5 µM). Structure–activity relationship (SAR) studies revealed that positions C-12 and C-16 are critical for activity, while molecular docking suggested that the selected analogs can engage in interactions with conserved residues within the ArnT catalytic site. Microbiological assays highlighted key structural features of the aromatic abietane skeleton in restoring colistin sensitivity in drug-resistant P. aeruginosa, and rationalized biological activity data to corroborate the quality of the selected scaffold in the development of cost-effective colistin resistance breakers.