Structural and functional insights of AmpG in muropeptide transport and multiple β-lactam antibiotics resistance

Nienping Chang, Hoyoung Kim, Uijin Kim, Yongju Cho, Youngki Yoo, Hyunsook Lee, Ji Won Kim, Min Sung Kim, Jaeho Lee, Young-Lag Cho, Kitae Kim, Dongeun Yong () and Hyun-Soo Cho ()
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Nienping Chang: Yonsei University
Hoyoung Kim: Yonsei University
Uijin Kim: Yonsei University
Yongju Cho: Yonsei University
Youngki Yoo: Yonsei University
Hyunsook Lee: Yonsei University College of Medicine
Ji Won Kim: Pohang University of Science and Technology
Min Sung Kim: Yonsei University
Jaeho Lee: LigaChem Biosciences Inc
Young-Lag Cho: LigaChem Biosciences Inc
Kitae Kim: Gyeongsang National University
Dongeun Yong: Yonsei University College of Medicine
Hyun-Soo Cho: Yonsei University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Anhydromuropeptide permease (AmpG) is a transporter protein located in the inner membrane of certain gram -negative bacteria, involved in peptidoglycan (PG) recycling and β-lactamase induction. Decreased AmpG function reduces resistance of antibiotic-resistant bacteria to β-lactam antibiotics. Therefore, AmpG-targeting inhibitors are promising ‘antibiotic adjuvants’. However, as the tertiary structure of AmpG has not yet been identified, the development of targeted inhibitors remains challenging. We present four cryo-electron microscopy (cryo-EM) structures: the apo-inward and apo-outward state structures and the inward-occluded and outward states complexed with the substrate GlcNAc-1,6-anhMurNAc. Through functional analysis and molecular dynamics (MD) simulations, we identified motif A, which stabilizes the outward state, substrate-binding pocket, and protonation-related residues. Based on the structure of AmpG and our experimental results, we propose a muropeptide transport mechanism for AmpG. A deeper understanding of its structure and transport mechanism provides a foundation for the development of antibiotic adjuvants.

Date: 2025
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DOI: 10.1038/s41467-025-61169-3

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