title: Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump.
abstract: Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for the development of effective EPIs, especially in light of constantly emerging resistance. Here, we describe EPIs that interact with periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump, change its structure in vivo, inhibit efflux of fluorescent probes, and potentiate the activities of antibiotics in Escherichia coli and other Gram-negative bacteria. Our findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.
authors: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
authors: Narges
authors: N
authors: Abdali
authors: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.|Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
authors: Jerry M
authors: JM
authors: Parks
authors: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
authors: Keith M
authors: KM
authors: Haynes
authors: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
authors: Julie L
authors: JL
authors: Chaney
authors: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.
authors: Adam T
authors: AT
authors: Green
authors: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
authors: David
authors: D
authors: Wolloscheck
authors: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
authors: John K
authors: JK
authors: Walker
authors: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
authors: Valentin V
authors: VV
authors: Rybenkov
authors: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.|Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
authors: Jerome
authors: J
authors: Baudry
authors: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.|Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
authors: Jeremy C
authors: JC
authors: Smith
authors: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
authors: Helen I
authors: HI
authors: Zgurskaya
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D055808:Drug Discovery; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins
keywords: Gram-negative bacteria; antibiotic resistance; efflux pump inhibitors; hyperporinated outer membrane