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Structure and inhibition mechanisms of Mycobacterium tuberculosis essential transporter efflux protein A

Author

Listed:
  • Nitesh Kumar Khandelwal

    (University of California San Francisco
    Oregon Health & Science University)

  • Meghna Gupta

    (University of California San Francisco
    Oregon Health & Science University)

  • James E. Gomez

    (Broad Institute of MIT and Harvard)

  • Sulyman Barkho

    (Broad Institute of MIT and Harvard)

  • Ziqiang Guan

    (Duke University Medical Center)

  • Ashley Y. Eng

    (Broad Institute of MIT and Harvard)

  • Tomohiko Kawate

    (Broad Institute of MIT and Harvard)

  • Sree Ganesh Balasubramani

    (University of California San Francisco)

  • Andrej Sali

    (University of California San Francisco)

  • Deborah T. Hung

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Robert M. Stroud

    (University of California San Francisco)

Abstract

A broad chemical genetic screen in Mycobacterium tuberculosis (Mtb) identified compounds (BRD-8000.3 and BRD-9327) that inhibit the essential efflux pump EfpA. To understand the mechanisms of inhibition, we determined the structures of EfpA with these inhibitors bound at 2.7-3.4 Å resolution. Our structures reveal different mechanisms of inhibition by the two inhibitors. BRD-8000.3 binds in a tunnel contacting the lipid bilayer and extending toward the central cavity to displace the fatty acid chain of a lipid molecule bound in the apo structure, suggesting its blocking of an access route for a natural lipidic substrate. Meanwhile, BRD-9327 binds in the outer vestibule without complete blockade of the substrate path to the outside, suggesting its possible inhibition of the movement necessary for alternate access of the transporter. Our results show EfpA as a potential lipid transporter, explain the basis of the synergy of these inhibitors and their potential for combination anti-tuberculosis therapy.

Suggested Citation

  • Nitesh Kumar Khandelwal & Meghna Gupta & James E. Gomez & Sulyman Barkho & Ziqiang Guan & Ashley Y. Eng & Tomohiko Kawate & Sree Ganesh Balasubramani & Andrej Sali & Deborah T. Hung & Robert M. Stroud, 2025. "Structure and inhibition mechanisms of Mycobacterium tuberculosis essential transporter efflux protein A," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58133-6
    DOI: 10.1038/s41467-025-58133-6
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