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Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms

Author

Listed:
  • Alina Ornik-Cha

    (Goethe-University Frankfurt)

  • Julia Wilhelm

    (Goethe-University Frankfurt)

  • Jessica Kobylka

    (Goethe-University Frankfurt)

  • Hanno Sjuts

    (Goethe-University Frankfurt
    Biologics Research, Sanofi-Aventis Deutschland GmbH)

  • Attilio V. Vargiu

    (University of Cagliari)

  • Giuliano Malloci

    (University of Cagliari)

  • Julian Reitz

    (Goethe-University Frankfurt
    Goethe-University Frankfurt)

  • Anja Seybert

    (Goethe-University Frankfurt
    Goethe-University Frankfurt)

  • Achilleas S. Frangakis

    (Goethe-University Frankfurt
    Goethe-University Frankfurt)

  • Klaas M. Pos

    (Goethe-University Frankfurt)

Abstract

Upon antibiotic stress Gram-negative pathogens deploy resistance-nodulation-cell division-type tripartite efflux pumps. These include a H+/drug antiporter module that recognizes structurally diverse substances, including antibiotics. Here, we show the 3.5 Å structure of subunit AdeB from the Acinetobacter baumannii AdeABC efflux pump solved by single-particle cryo-electron microscopy. The AdeB trimer adopts mainly a resting state with all protomers in a conformation devoid of transport channels or antibiotic binding sites. However, 10% of the protomers adopt a state where three transport channels lead to the closed substrate (deep) binding pocket. A comparison between drug binding of AdeB and Escherichia coli AcrB is made via activity analysis of 20 AdeB variants, selected on basis of side chain interactions with antibiotics observed in the AcrB periplasmic domain X-ray co-structures with fusidic acid (2.3 Å), doxycycline (2.1 Å) and levofloxacin (2.7 Å). AdeABC, compared to AcrAB-TolC, confers higher resistance to E. coli towards polyaromatic compounds and lower resistance towards antibiotic compounds.

Suggested Citation

  • Alina Ornik-Cha & Julia Wilhelm & Jessica Kobylka & Hanno Sjuts & Attilio V. Vargiu & Giuliano Malloci & Julian Reitz & Anja Seybert & Achilleas S. Frangakis & Klaas M. Pos, 2021. "Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27146-2
    DOI: 10.1038/s41467-021-27146-2
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    References listed on IDEAS

    as
    1. Heng-Keat Tam & Wuen Ee Foong & Christine Oswald & Andrea Herrmann & Hui Zeng & Klaas M. Pos, 2021. "Allosteric drug transport mechanism of multidrug transporter AcrB," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    2. Satoshi Murakami & Ryosuke Nakashima & Eiki Yamashita & Takashi Matsumoto & Akihito Yamaguchi, 2006. "Crystal structures of a multidrug transporter reveal a functionally rotating mechanism," Nature, Nature, vol. 443(7108), pages 173-179, September.
    3. Chih-Chia Su & Linxiang Yin & Nitin Kumar & Lei Dai & Abhijith Radhakrishnan & Jani Reddy Bolla & Hsiang-Ting Lei & Tsung-Han Chou & Jared A. Delmar & Kanagalaghatta R. Rajashankar & Qijing Zhang & Ye, 2017. "Structures and transport dynamics of a Campylobacter jejuni multidrug efflux pump," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    4. Marie Glavier & Dhenesh Puvanendran & Dimitri Salvador & Marion Decossas & Gilles Phan & Cyril Garnier & Elisa Frezza & Quentin Cece & Guy Schoehn & Martin Picard & Jean-Christophe Taveau & Laetitia D, 2020. "Antibiotic export by MexB multidrug efflux transporter is allosterically controlled by a MexA-OprM chaperone-like complex," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    5. Ryosuke Nakashima & Keisuke Sakurai & Seiji Yamasaki & Kunihiko Nishino & Akihito Yamaguchi, 2011. "Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket," Nature, Nature, vol. 480(7378), pages 565-569, December.
    6. Xiaodong Shi & Muyuan Chen & Zhili Yu & James M. Bell & Hans Wang & Isaac Forrester & Heather Villarreal & Joanita Jakana & Dijun Du & Ben F. Luisi & Steven J. Ludtke & Zhao Wang, 2019. "In situ structure and assembly of the multidrug efflux pump AcrAB-TolC," Nature Communications, Nature, vol. 10(1), pages 1-6, December.
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