Identification and Structure-Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli.
Keith M Haynes, Narges Abdali, Varsha Jhawar, Helen I Zgurskaya, Jerry M Parks, Adam T Green, Jerome Baudry, Valentin V Rybenkov, Jeremy C Smith, John K Walker
Author Information
Keith M Haynes: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine , St Louis, Missouri 63104, United States.
Narges Abdali: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
Varsha Jhawar: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
Helen I Zgurskaya: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
Jerry M Parks: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States. ORCID
Adam T Green: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.
Jerome Baudry: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.
Valentin V Rybenkov: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States. ORCID
Jeremy C Smith: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.
John K Walker: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine , St Louis, Missouri 63104, United States. ORCID
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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