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

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. In this paper, we present initial optimization efforts and structure–activity relationships around one of those previously described hits, NSC 60339 (1). Finally, 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.

Authors:
 [1];  [2];  [2];  [2]; ORCiD logo [3];  [3];  [4]; ORCiD logo [2];  [4]; ORCiD logo [5]
  1. Saint Louis Univ., St. Louis, MO (United States). School of Medicine. Dept. of Pharmacological and Physiological Science
  2. Univ. of Oklahoma, Norman, OK (United States). Dept. of Chemistry and Biochemistry
  3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division. UT/ORNL Center for Molecular Biophysics; Univ. of Tennessee, Knoxville, TN (United States). Graduate School of Genome Science and Technology
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division. UT/ORNL Center for Molecular Biophysics; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology
  5. Saint Louis Univ., St. Louis, MO (United States). School of Medicine. Dept. of Pharmacological and Physiological Science. Dept. of Chemistry
Publication Date:
Research Org.:
Saint Louis Univ., St. Louis, MO (United States); Univ. of Oklahoma, Norman, OK (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States); Univ. of Saint Louis School of Medicine (United States)
OSTI Identifier:
1376432
Grant/Contract Number:
AC05-00OR22725; AI052293
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 60; Journal Issue: 14; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Haynes, Keith M., Abdali, Narges, Jhawar, Varsha, Zgurskaya, Helen I., Parks, Jerry M., Green, Adam T., Baudry, Jerome, Rybenkov, Valentin V., Smith, Jeremy C., and Walker, John K. Identification and Structure–Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli. United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.7b00453.
Haynes, Keith M., Abdali, Narges, Jhawar, Varsha, Zgurskaya, Helen I., Parks, Jerry M., Green, Adam T., Baudry, Jerome, Rybenkov, Valentin V., Smith, Jeremy C., & Walker, John K. Identification and Structure–Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli. United States. doi:10.1021/acs.jmedchem.7b00453.
Haynes, Keith M., Abdali, Narges, Jhawar, Varsha, Zgurskaya, Helen I., Parks, Jerry M., Green, Adam T., Baudry, Jerome, Rybenkov, Valentin V., Smith, Jeremy C., and Walker, John K. 2017. "Identification and Structure–Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli". United States. doi:10.1021/acs.jmedchem.7b00453.
@article{osti_1376432,
title = {Identification and Structure–Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli},
author = {Haynes, Keith M. and Abdali, Narges and Jhawar, Varsha and Zgurskaya, Helen I. and Parks, Jerry M. and Green, Adam T. and Baudry, Jerome and Rybenkov, Valentin V. and Smith, Jeremy C. and Walker, John K.},
abstractNote = {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. In this paper, we present initial optimization efforts and structure–activity relationships around one of those previously described hits, NSC 60339 (1). Finally, 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.},
doi = {10.1021/acs.jmedchem.7b00453},
journal = {Journal of Medicinal Chemistry},
number = 14,
volume = 60,
place = {United States},
year = 2017,
month = 6
}

Journal Article:
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