National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
R01AI108889
United States
National Science Foundation (NSF, United States)
MCB1506420
United States
American Cancer Society
129844-PF-17-135-01-TBE
United States
Department of Defense (DOD, United States)
W81XWH-16-1-0153
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM093825
United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS108151
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM121994
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
T32GM881188
United States
Citation
Journal: Nat Chem Biol / Year: 2022 Title: Structural basis for inhibition of the drug efflux pump NorA from Staphylococcus aureus. Authors: Douglas N Brawley / David B Sauer / Jianping Li / Xuhui Zheng / Akiko Koide / Ganesh S Jedhe / Tiffany Suwatthee / Jinmei Song / Zheng Liu / Paramjit S Arora / Shohei Koide / Victor J Torres ...Authors: Douglas N Brawley / David B Sauer / Jianping Li / Xuhui Zheng / Akiko Koide / Ganesh S Jedhe / Tiffany Suwatthee / Jinmei Song / Zheng Liu / Paramjit S Arora / Shohei Koide / Victor J Torres / Da-Neng Wang / Nathaniel J Traaseth / Abstract: Membrane protein efflux pumps confer antibiotic resistance by extruding structurally distinct compounds and lowering their intracellular concentration. Yet, there are no clinically approved drugs to ...Membrane protein efflux pumps confer antibiotic resistance by extruding structurally distinct compounds and lowering their intracellular concentration. Yet, there are no clinically approved drugs to inhibit efflux pumps, which would potentiate the efficacy of existing antibiotics rendered ineffective by drug efflux. Here we identified synthetic antigen-binding fragments (Fabs) that inhibit the quinolone transporter NorA from methicillin-resistant Staphylococcus aureus (MRSA). Structures of two NorA-Fab complexes determined using cryo-electron microscopy reveal a Fab loop deeply inserted in the substrate-binding pocket of NorA. An arginine residue on this loop interacts with two neighboring aspartate and glutamate residues essential for NorA-mediated antibiotic resistance in MRSA. Peptide mimics of the Fab loop inhibit NorA with submicromolar potency and ablate MRSA growth in combination with the antibiotic norfloxacin. These findings establish a class of peptide inhibitors that block antibiotic efflux in MRSA by targeting indispensable residues in NorA without the need for membrane permeability.
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