Abstract
Colistin is a last-resort 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). Here, semisynthetic analogues of hit were designed, synthetized, and tested against colistin-resistant Pseudomonas aeruginosa strains including clinical isolates to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling indicated that for a more efficient colistin adjuvant activity, likely resulting from inhibition of the ArnT activity by the selected compounds and therefore from their interaction with the catalytic site of ArnT, an ent-beyerane scaffold is required along with an oxalate-like group at C-18/C-19 or a sugar residue at C-19 to resemble L-Ara4N. The ent-beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors.
Highlights
Control of infections has long been a serious clinical concern and the discovery of antibiotics during the 1930s to 1960s opened the door to current antimicrobial drug discovery.[1]
This can have devastating effects if no other therapeutic strategies are uncovered to combat infections, including those associated with P. aeruginosa in cystic fibrosis lungs
Through the combination of computational modeling, organic synthesis, and biological evaluations in a concerted multidisciplinary strategy, we explore structure− activity relationships (SAR) around the initial diterpene hit 1 and validate its scaffold for the production of novel antibacterial agents for the treatment of colistin-resistant infections
Summary
Control of infections has long been a serious clinical concern and the discovery of antibiotics during the 1930s to 1960s opened the door to current antimicrobial drug discovery.[1]. One of the mechanisms of resistance consists in the covalent modification of LPS by the addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) or phosphoethanolamine groups to lipid A, which decreases the overall charge of LPS and, as a result, the binding affinity of the cationic
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