Pyrylium derivatives as outer membrane permeabilizers against MDR gram-negative bacteria via multi-target mode of action

The prevalence of MDR Gram-negative bacteria has posed a great impetus for the discovery of new therapeutic approaches. Here, we synthesized a series of pyrylium derivatives as antibiotic adjuvants based on IMB-0042, and evaluated their activities against Acinetobacter baumannii (A. baumannii) and Escherichia coli (E. coli). Compound 4a significantly synergized polymyxin B in combating A. baumannii and E. coli both in vitro and on the infected Galleria mellonella models. Furthermore, we identified 4a to be an effective perturbant of the Gramnegative outer membrane (OM) through the blockage on LptA/LptC interaction via targeting Met47 in LptA. And cationic pyrylium reduced the OM densification by electrostatic interaction with anion-rich lipopolysaccharide (LPS). Thus, pyrylium derivatives constitute a new class of multi-target OM permeabilizers, which can significantly potentiate antibiotics against MDR Gram-negative bacteria.