2. Academic Validation
  3. Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters

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

  • ACS Infect Dis. 2018 Nov 9;4(11):1540-1545. doi: 10.1021/acsinfecdis.8b00161.
Wooseong Kim 1,  Andrew D Steele 2,  Wenpeng Zhu 3,  Erika E Csatary 2,  Nico Fricke 3,  Madeline M Dekarske 2,  Elamparithi Jayamani 1,  Wen Pan 1,  Bumsup Kwon 4,  Isabelle F Sinitsa 5,  Jake L Rosen 2,  Annie L Conery 6 7,  Beth Burgwyn Fuchs 1,  Petia M Vlahovska 8,  Frederick M Ausubel 6 7,  Huajian Gao 3,  William M Wuest 2,  Eleftherios Mylonakis 1
Affiliations

Affiliations

  • 1 Division of Infectious Diseases , Rhode Island Hospital and Warren Alpert Medical School of Brown University , 593 Eddy Street , Providence , Rhode Island 02903 , United States.
  • 2 Department of Chemistry and Emory Antibiotic Resistance Center , Emory University , 1515 Dickey Drive , Atlanta , Georgia 30322 , United States.
  • 3 School of Engineering , Brown University , 184 Hope Street , Providence , Rhode Island 02903 , United States.
  • 4 Division of Neurology , Rhode Island Hospital and Warren Alpert Medical School of Brown University , 593 Eddy Street , Providence , Rhode Island 02903 , United States.
  • 5 Department of Chemistry , Temple University , 1901 N. 13th Street , Philadelphia , Pennsylvania 19122 , United States.
  • 6 Department of Molecular Biology , Massachusetts General Hospital , 185 Cambridge Street , Boston , Massachusetts 02115 , United States.
  • 7 Department of Genetics , Harvard Medical School , 185 Cambridge Street , Boston , Massachusetts 02115 , United States.
  • 8 Department of Engineering Sciences and Applied Mathematics , Northwestern University , 2145 Sheridan Road , Evanston , Illinois 60208 , United States.
PMID: 30132650 DOI: 10.1021/acsinfecdis.8b00161
Abstract

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.

Keywords

MD simulations; MRSA; SAR; antibiotics; membrane-active agent; persisters.

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