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

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 () and Robert M. Stroud ()
Additional contact information
Nitesh Kumar Khandelwal: University of California San Francisco
Meghna Gupta: University of California San Francisco
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
Robert M. Stroud: University of California San Francisco

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58133-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58133-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58133-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().