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 t...

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Bibliographic Details
Published in:ACS infectious diseases 2021-03, Vol.7 (3), p.535-543
Main Authors: Zhang, Zinan, Ortega, Dominic, Rush, Anthony, Blankenship, Lauren R., Cheng, Zi Jun, Moore, Rebecca E., Tran, Minh L. N., Sandoval, Lucero G., Aboulhosn, Kareem, Watanabe, Seiichiro, Cortez, Kendra S., Perlman, David H., Semmelhack, Martin F., Miller Conrad, Laura C.
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - pharmacology
Anti-Bacterial Agents - therapeutic use
Antimicrobial Cationic Peptides
Colistin
Pseudomonas aeruginosa
Pyocyanine
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Summary: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.
ISSN:2373-8227
2373-8227
DOI:10.1021/acsinfecdis.0c00160