The AhR ligand phthiocol and vitamin K analogs as Pseudomonas aeruginosa quorum sensing inhibitors

Tianyuan Jia; Dongjing Liu; Xianbiao Bi; Menglu Li; Zhao Cai; Jiapeng Fu; Zhi Liu; Pengyao Wu; Xue Ke; Aiqun Jia; Guoliang Zhang; Guobao Li; Liang Yang

doi:10.3389/fmicb.2022.896687

The AhR ligand phthiocol and vitamin K analogs as Pseudomonas aeruginosa quorum sensing inhibitors

Front Microbiol. 2022 Sep 14:13:896687. doi: 10.3389/fmicb.2022.896687. eCollection 2022.

Authors

Tianyuan Jia¹, Dongjing Liu², Xianbiao Bi¹, Menglu Li^{1

2}, Zhao Cai¹, Jiapeng Fu², Zhi Liu², Pengyao Wu², Xue Ke², Aiqun Jia³, Guoliang Zhang², Guobao Li², Liang Yang^{1

2

4}

Affiliations

¹ School of Medicine, Southern University of Science and Technology, Shenzhen, China.
² Shenzhen Third People's Hospital, National Clinical Research Center for Infectious Disease, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.
³ School of Pharmaceutical Sciences, Hainan University, Haikou, China.
⁴ Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, China.

Abstract

The aryl hydrocarbon receptor (AhR) protein senses microbial-secreted metabolites to trigger the host's innate immune system. The Pseudomonas quinolone signal (PQS) and Mycobacterium tuberculosis (MTb) metabolite phthiocol (Pht) are both ligands of AhR with similar chemical structures. As PQS is an essential quorum-sensing molecule that regulates a wide range of virulence factors in Pseudomonas aeruginosa, we hypothesized that Pht and its analogs are potential P. aeruginosa quorum-sensing inhibitors (QSIs) with immune-modulating functions. In this study, we demonstrated that Pht was able to inhibit the P. aeruginosa pqs QS system and reduce both biofilm formation and the production of pyocyanin. Molecular docking analysis suggested that Pht competes with PQS at the binding site of its receptor, PqsR. An electrophoretic mobility shift assay confirmed the Pht-PqsR interaction and showed that Pht attenuated PqsR from binding to the pqsA promoter. Proteomic analysis showed that synthesis of the key pqs QS proteins decreased upon the addition of Pht to the bacterial cultures. Furthermore, Pht analogs vitamins K₁ (Phylloquinone), K₂ (Menaquinones), and K₃ (Menadione) were also showed to inhibit the P. aeruginosa pqs QS system while able to activate the AhR signaling pathways. Our study suggests that the AhR ligands Pht and its vitamin K analogs are promising QSIs for the alternative treatment of P. aeruginosa infections.

Keywords: Pseudomonas aeruginosa; Pseudomonas quinolone signal; aryl hydrocarbon receptor; phthiocol; vitamin K.