Currently, conventional antibiotics struggle to treat resistant and persistent bacteria. Identified in a high-throughput screen, non-thiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist (nTZDpa) kills not only growing but also persistent Staphylococcus aureus. Furthermore, nTZDpa exhibits low probabilities of resistance development, a hallmark of membrane mechanisms. Additionally, nTZDpa functions synergistically with the aminoglycosides, such that it restores gentamicin activity against persister cells, and acts via a membrane permeabilization mechanism. However, nTZDpa lyses red blood cells and thus is not a viable antimicrobial. Our previous lead, while potent and non-toxic to red blood cells, killed renal cells. Therefore, our current synthetic efforts have been toward designing informed nTZDpa analogs that maintain potency against both growing and persistent S. aureus while reducing renal toxicity.

Repurposing nTZDpa: An antimicrobial effective against growing and persistent Staphylococcus aureus

ACS Fall 2021

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