Professor Nate Traaseth and colleagues in the NYU Department of Chemistry and Langone School of Medicine have determined that the structure of a bacterial "drug pump" leads to a new way to counter hospital borne infection. By revealing the structure of a protein used by bacteria to pump out antibiotics, the research team designed an early-stage therapeutic that sabotages the pump and restores the effectiveness of antibiotics. The study was published in Nature Chemical Biology, entitled "Structural basis for inhibition of the drug efflux pump NorA from Staphylococcus aureus." NYU School of Medicine Professors Da-Neng Wang and Shohei Koide were corresponding authors along with Professor Traaseth. Doug Brawley, a jointly supervised doctoral student in the Traaseth and Wang labs, was the first author. Other NYU Chemistry authors include postdoctoral fellows Jianping Li and Ganesh Jedhe, grad student Tiffany Suwatthee, and Professor Paramjit S. Arora.
This work relied on a strong team of laboratories across NYU possessing expertise in membrane protein structural biology and biochemistry (Traaseth and Wang), protein engineering (Koide), S. aureus biology (Victor Torres, NYU Microbiology), and organic chemistry and peptide design (Arora).
Click here to read the full article in Nature Chem Bio.
Click here to read the NYU Langone press release.
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 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.
This research was supported by the National Science Foundation and the National Institutes of Health, the American Cancer Society, the U.S. Department of Defense and the Burroughs Wellcome Fund.