Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters

Conventional
antibiotics are not effective in treating infections
caused by drug-resistant or persistent nongrowing bacteria, creating
a dire need for the development of new antibiotics. We report that
the small molecule nTZDpa, previously characterized as a nonthiazolidinedione
peroxisome proliferator-activated receptor gamma partial agonist,
kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S. aureus exhibited no detectable development of resistance to nTZDpa, and
the compound acted synergistically with aminoglycosides. We improved
both the potency and selectivity of nTZDpa against MRSA membranes
compared to mammalian membranes by leveraging synthetic chemistry
guided by molecular dynamics simulations. These studies provide key
insights into the design of selective and potent membrane-active antibiotics
effective against bacterial persisters.