Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump.
Narges Abdali, Jerry M Parks, Keith M Haynes, Julie L Chaney, Adam T Green, David Wolloscheck, John K Walker, Valentin V Rybenkov, Jerome Baudry, Jeremy C Smith, Helen I Zgurskaya
Author Information
Narges Abdali: 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.
Keith M Haynes: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
Julie L Chaney: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
Adam T Green: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.
David Wolloscheck: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
John K Walker: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
Valentin V Rybenkov: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
Jerome Baudry: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.
Jeremy C Smith: UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.
Helen I Zgurskaya: Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
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.
