Colistin is a last resort treatment option for many multidrug resistant Gram-negative bacteria. However, colistin resistance immediately appeared as colistin was introduced in clinical setting. The covalent addition of L-aminoarabinose to the lipid A moiety of LPS is the main colistin resistance mechanism in the human pathogen Pseudomonas aeruginosa.
Pseudomonas aeruginosa, is among the bacteria for which antibiotics are urgently needed. In Cystic Fibrosis (CF), colistin has been used for decades suggesting that resistance to this antibiotic might become soon critical for CF patients. Indeed, an increase of colistin-resistant P. aeruginosa isolates in CF has been recently reported.
The antibacterial activity of colistin relies on its interaction with LPS. Aminoarabinosylation of the lipid A moiety of LPS is strictly required for the development of colistin resistance in P. aeruginosa. Therefore, the main objective of this project is to develop small molecules that revert colistin resistance by targeting lipid A aminoarabinosylation.
Taking advantage of the resolved structure of the aminoarabinose transferase, which catalyzes the last step of lipid A aminoarabinosylation, and using a structure-guided in silico approach, we have identified a short list of candidate hits from the screening of a library of natural compounds. Among them we have identified one compound, named BBN149, which is active at relatively low concentration in reversing colistin resistance to colistin sensitivity of a P. aeruginosa tester strain.
Growth-inhibition assays and computational analysis strongly suggest that BBN149 is an inhibitor of ArnT activity.
The present project comprises the following aims: modification of BBN149 by medicinal chemistry to produce derivatives with optimized potency and specificity; analysis of the efficacy of BBN149 and its derivatives on different model systems.
