Ricerc@Sapienza

Pseudomonas aeruginosa, is among the bacteria for which antibiotics are urgently needed. At present, the old antibiotic colistin, is used as the last-resort treatment. 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. Growth-inhibition assays of a colistin-resistant tester strain led to the identification of one lead compound, which was active at relatively low concentration.

The proposed project comprises the following aims: optimization of potency and specificity of the lead compound; analysis of the efficacy of lead inhibitors on different model systems. Each aim is accomplished through the execution of different tasks, carried out by a multidisciplinary team.
Modification of the lead compound through combined computational and medicinal chemistry followed by activity testing will allow the development of small molecule/s that meet the criteria for clinical use, such as potent IC50, water solubility and low off-target effects.
As few treatment options exist for colistin-resistant Gram-negative bacteria, development of new drugs is of critical value to postpone the advancement of the post-antibiotic era.