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

• DOI: 10.1021/acsinfecdis.6b00167
• Publication Date: 2016-10-21T21:58:50Z
• Authors: 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
• Keywords: Efflux; Druggability; Multidrug Resistance-Associated Proteins

Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities antibiotics and reduce bacterial virulence. Identification new druggable sites for inhibition critical the development effective EPIs, especially in light constantly emerging resistance. Here, we describe EPIs interact with periplasmic membrane fusion proteins, components responsible activation transporter recruitment outer-membrane channel. The discovered bind AcrA, component prototypical AcrAB-TolC pump, change its structure vivo, inhibit fluorescent probes, potentiate Escherichia coli other Gram-negative bacteria. Our findings expand chemical mechanistic diversity suggest mechanism regulation pump assembly activity, provide path reviving resistant