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

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.

doi:10.1021/acs.jmedchem.7b00453

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

Journal Article · Mon Jun 26 00:00:00 EDT 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b00453· OSTI ID:1376432

Haynes, Keith M. ^[1]; Abdali, Narges ^[2]; Jhawar, Varsha ^[2]; Zgurskaya, Helen I. ^[2]; ^[3]; Green, Adam T. ^[3]; Baudry, Jerome ^[4]; ^[2]; Smith, Jeremy C. ^[4]; ^[5]

Saint Louis Univ., St. Louis, MO (United States). School of Medicine. Dept. of Pharmacological and Physiological Science
Univ. of Oklahoma, Norman, OK (United States). Dept. of Chemistry and Biochemistry
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
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
Saint Louis Univ., St. Louis, MO (United States). School of Medicine. Dept. of Pharmacological and Physiological Science. Dept. of Chemistry

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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Saint Louis Univ., St. Louis, MO (United States); Univ. of Oklahoma, Norman, OK (United States)

Sponsoring Organization:: National Inst. of Health (NIH) (United States); USDOE; Univ. of Saint Louis School of Medicine (United States)

Contributing Organization:: Univ. of Tennessee, Knoxville, TN (United States)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1376432

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 14 Vol. 60; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Efflux pump inhibitors for bacterial pathogens: From bench to bedside Pathania, Ranjana; Sharma, Atin; Gupta, VivekKumar Indian Journal of Medical Research, Vol. 149, Issue 2 https://doi.org/10.4103/ijmr.ijmr_2079_17	journal	January 2019
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