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Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump

by Jerry Parks, Adam Green, Jerome Baudry, Jeremy Smith, et al.

Abstract 

Once antibiotics have entered the cell by crossing the outer membrane (inset, top), they enter the efflux pump protein shown in yellow near the inner membrane (bottom) only to be pumped back out of the cell (upward). ORNL used the Titan supercomputer to identify molecules that target the “red” proteins and potentially disable the efflux pump by preventing it from assembling properly. Once antibiotics have entered the cell by crossing the outer membrane (inset, top), they enter the efflux pump protein shown in yellow near the inner membrane (bottom) only to be pumped back out of the cell (upward). ORNL used the Titan supercomputer to identify molecules that target the “red” proteins and potentially disable the efflux pump by preventing it from assembling properly. Image by Jerry Parks/ORNL (hi-res image)
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.

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Publication Citation

ACS Infectious Diseases 2016
DOI: 10.1021/acsinfecdis.6b00167

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