Discovery of a widespread chemical signalling pathway in the Bacteroidota

Luis Linares-Otoya, Jaden D. Shirkey, Bhuwan Khatri Chhetri, Amira Mira, Abhishek Biswas, Samuel L. Neff, Maria V. Linares-Otoya, Ye Chen, Julio V. Campos-Florian, Mayar L. Ganoza-Yupanqui, Philip D. Jeffrey, Frederick M. Hughson and Mohamed S. Donia ()
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Luis Linares-Otoya: Princeton University
Jaden D. Shirkey: Princeton University
Bhuwan Khatri Chhetri: Princeton University
Amira Mira: Princeton University
Abhishek Biswas: Princeton University
Samuel L. Neff: Princeton University
Maria V. Linares-Otoya: National University of Trujillo
Ye Chen: Princeton University
Julio V. Campos-Florian: National University of Trujillo
Mayar L. Ganoza-Yupanqui: National University of Trujillo
Philip D. Jeffrey: Princeton University
Frederick M. Hughson: Princeton University
Mohamed S. Donia: Princeton University

Nature, 2025, vol. 646, issue 8084, 423-432

Abstract: Abstract Considerable advances have been made in characterizing bioactive molecules secreted by bacteria, yet the regulatory elements controlling their production remain largely understudied. Here we identify and characterize the N-acyl-cyclolysine (ACL) system—a cell-density-dependent chemical signalling system specific to and widespread in the phylum Bacteroidota (formerly Bacteroidetes)—and show that it regulates the expression of co-localized operons encoding diverse secreted molecules. Using genetic and biochemical analyses, combined with structural studies of a key biosynthetic enzyme, AclA, we elucidate the molecular structure of various ACLs and their complete biosynthetic pathway involving l-lysine acylation and ATP-dependent cyclization. Furthermore, we find that secreted ACLs are sensed by a dedicated transcription factor, AclR, resulting in the expression of associated operons and the autoinduction of ACL biosynthesis. Moreover, we show that different Bacteroidota strains produce structurally diverse ACLs and encode transcription factors with varying ligand specificities. Finally, we find that the acl circuit is widely distributed and transcribed in human gut and oral microbiome samples, with clear evidence for an active role in regulating associated operons under host colonization conditions. Understanding the function of the ACL system in different contexts has the potential to reveal details about the biology, ecology and chemistry of the Bacteroidota and how members of this phylum interact with their environments and hosts.

Date: 2025
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DOI: 10.1038/s41586-025-09418-9

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