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

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• 作者：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
• 刊名：ACS Infectious Diseases
• 出版年：2017
• 出版时间：January 13, 2017
• 年：2017
• 卷：3
• 期：1
• 页码：89-98
• 全文大小：603K
• ISSN：2373-8227

文摘

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.