Inhibition of colistin resistance in Pseudomonas aeruginosa strains

Colistin is a cationic peptide that targets electrostatically the lipid A component of lipopolysaccharide. Colistin resistance can occur through lipid A modifications that, by changing its negative charge, inhibit colistin binding. In Pseudomonas aeruginosa the addition of 4-amino-4- deoxy-L-arabinose to lipid A, mediated by ArnT, is the prevalent mechanism of resistance to colistin. Previously, the diterpene BBN149 (10.1093/jac/dkaa200) has been identified as a putative inhibitor of ArnT and demonstrated to act as colistin adjuvant against colistin-resistant P. aeruginosa planktonic cultures. As biofilms are very relevant for the persistence of bacterial infection, we test the colistin adjuvant activity of BBN149 and its derivatives in P. aeruginosa biofilms. Biofilms treated with different combinations of colistin and adjuvants were quantified by crystal violet, metabolic assay and viable cell counting. P. aeruginosa biofilms of reference and clinical strains were tested. The results showed a good activity of colistin against biofilms, which was further improved by the compounds. Interestingly, the adjuvant activity of the compounds was more effective against the clinical strain.