Antibiotic Adjuvant Activity Revealed in a Photoaffinity Approach to Determine the Molecular Target of Antipyocyanin Compounds

Infections with Pseudomonas aeruginosa are a looming threat to public health. New treatment strategies are needed to combat this pathogen, for example, by blocking the production of virulence factors like pyocyanin. A photoaffinity analogue of an antipyocyanin compound was developed to interrogate the inhibitor's molecular mechanism of action. While we sought to develop antivirulence inhibitors, the proteomics results suggested that the compounds had antibiotic adjuvant activity. Unexpectedly, we found that these compounds amplify the bactericidal activity of colistin, a well-characterized antibiotic, suggesting they may represent a first-in-class antibiotic adjuvant therapy. Analogues have the potential not only to widen the therapeutic index of cationic antimicrobial peptides like colistin, but also to be effective against colistin-resistant strains, strengthening our arsenal to combat P. aeruginosa infections.