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

Wooseong Kim, Andrew D. Steele, Wenpeng Zhu, Erika E. Csatary, Nico Fricke, Madeline M. Dekarske, Elamparithi Jayamani, Wen Pan, Bumsup Kwon, Isabelle F. Sinitsa, Jake L. Rosen, Annie L. Conery, Beth Burgwyn Fuchs, Petia M. Vlahovska, Frederick M. Ausubel, Huajian Gao, William M. Wuest, Eleftherios Mylonakis

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1540-1545
Number of pages6
JournalACS Infectious Diseases
Issue number11
StatePublished - Nov 9 2018


  • MD simulations
  • MRSA
  • SAR
  • antibiotics
  • membrane-active agent
  • persisters

ASJC Scopus subject areas

  • Infectious Diseases


Dive into the research topics of 'Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters'. Together they form a unique fingerprint.

Cite this