AB569, a nontoxic chemical tandem that kills major human pathogenic bacteria
Cameron T. McDaniel, Warunya Panmanee, Geoffrey L. Winsor, Erin Gill, Claire Bertelli, Michael J. Schurr, Prateek Dongare, Andrew T. Paul, Seung-Hyun B. Ko, Gee W. Lau, Nupur Dasgupta, Amy L. Bogue, William E. Miller, Joel E. Mortensen, David B. Haslam, Phillip Dexheimer, Daniel A. Muruve, Bruce J. Aronow, Malcolm D. E. Forbes, Marek Danilczuk, Fiona S. L. Brinkman, Robert E. W. Hancock, Thomas J. Meyer, and Daniel J. Hassett
PNAS March 3, 2020 117 (9) 4921-4930; first published February 18, 2020
Antibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO2−) and Na2-EDTA (disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism Pseudomonas aeruginosa in biofilms and in a murine chronic lung infection model. AB569 was not toxic to human cell lines at bactericidal concentrations using a basic viability assay. RNA-Seq analyses upon treatment of P. aeruginosa with AB569 revealed a catastrophic loss of the ability to support core pathways encompassing DNA, RNA, protein, ATP biosynthesis, and iron metabolism. Electrochemical analyses elucidated that AB569 produced more stable SNO proteins, potentially explaining one mechanism of bacterial killing. Our data implicate that AB569 is a safe and effective means to kill pathogenic bacteria, suggesting that simple strategies could be applied with highly advantageous therapeutic/toxicity index ratios to pathogens associated with a myriad of periepithelial infections and related disease scenarios.