2. Academic Validation
  3. Identification and Structure-Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli

Identification and Structure-Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli

  • J Med Chem. 2017 Jul 27;60(14):6205-6219. doi: 10.1021/acs.jmedchem.7b00453.
Keith M Haynes 1,  Narges Abdali 2,  Varsha Jhawar 2,  Helen I Zgurskaya 2,  Jerry M Parks 3 4,  Adam T Green 3 4,  Jerome Baudry 3 5,  Valentin V Rybenkov 2,  Jeremy C Smith 3 5,  John K Walker 1 6
Affiliations

Affiliations

  • 1 Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine , St Louis, Missouri 63104, United States.
  • 2 Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
  • 3 UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.
  • 4 Graduate School of Genome Science and Technology, University of Tennessee , Knoxville, Tennessee 37996, United States.
  • 5 Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
  • 6 Department of Chemistry, Saint Louis University , St. Louis, Missouri 63104, United States.
PMID: 28650638 DOI: 10.1021/acs.jmedchem.7b00453
Abstract

In Gram-negative bacteria, efflux pumps are able to prevent effective cellular concentrations from being achieved for a number of Antibiotics. Small molecule adjuvants that act as efflux pump inhibitors (EPIs) have the potential to reinvigorate existing Antibiotics that are currently ineffective due to efflux mechanisms. Through a combination of rigorous experimental screening and in silico virtual screening, we recently identified novel classes of EPIs that interact with the membrane fusion protein AcrA, a critical component of the AcrAB-TolC efflux pump in Escherichia coli. Herein, we present initial optimization efforts and structure-activity relationships around one of those previously described hits, NSC 60339 (1). From these efforts we identified two compounds, SLUPP-225 (17h) and SLUPP-417 (17o), which demonstrate favorable properties as potential EPIs in E. coli cells including the ability to penetrate the outer membrane, improved inhibition of efflux relative to 1, and potentiation of the activity of novobiocin and erythromycin.

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