Analysis of Regulatory Mechanism of AcrB and CpxR on Colistin Susceptibility Based on Transcriptome and Metabolome of Salmonella Typhimurium

Bibliographic Details
Title: Analysis of Regulatory Mechanism of AcrB and CpxR on Colistin Susceptibility Based on Transcriptome and Metabolome of Salmonella Typhimurium
Authors: Ya-Jun Zhai, Pei-Yi Liu, Xing-Wei Luo, Jun Liang, Ya-Wei Sun, Xiao-Die Cui, Dan-Dan He, Yu-Shan Pan, Hua Wu, Gong-Zheng Hu
Source: Microbiology Spectrum, Vol 11, Iss 4 (2023)
Publisher Information: American Society for Microbiology, 2023.
Publication Year: 2023
Collection: LCC:Microbiology
Subject Terms: colistin susceptibility, AcrB, CpxR, transcriptome, metabolome, Microbiology, QR1-502
More Details: ABSTRACT With the increasing and inappropriate use of colistin, the emerging colistin-resistant isolates have been frequently reported during the last few decades. Therefore, new potential targets and adjuvants to reverse colistin resistance are urgently needed. Our previous study has confirmed a marked increase of colistin susceptibility (16-fold compared to the wild-type Salmonella strain) of cpxR overexpression strain JSΔacrBΔcpxR::kan/pcpxR (simplified as JSΔΔ/pR). To searching for potential new drug targets, the transcriptome and metabolome analysis were carried out in this study. We found that the more susceptible strain JSΔΔ/pR displayed striking perturbations at both the transcriptomics and metabolomics levels. The virulence-related genes and colistin resistance-related genes (CRRGs) were significantly downregulated in JSΔΔ/pR. There were significant accumulation of citrate, α-ketoglutaric acid, and agmatine sulfate in JSΔΔ/pR, and exogenous supplement of them could synergistically enhance the bactericidal effect of colistin, indicating that these metabolites may serve as potential adjuvants for colistin therapy. Additionally, we also demonstrated that AcrB and CpxR could target the ATP and reactive oxygen species (ROS) generation, but not proton motive force (PMF) production pathway to potentiate antibacterial activity of colistin. Collectively, these findings have revealed several previously unknown mechanisms contributing to increased colistin susceptibility and identified potential targets and adjuvants for potentiating colistin treatment of Salmonella infections. IMPORTANCE Emergence of multidrug-resistant (MDR) Gram-negative (G-) bacteria have led to the reconsideration of colistin as the last-resort therapeutic option for health care-associated infections. Finding new drug targets and strategies against the spread of MDR G- bacteria are global challenges for the life sciences community and public health. In this paper, we demonstrated the more susceptibility strain JSΔΔ/pR displayed striking perturbations at both the transcriptomics and metabolomics levels and revealed several previously unknown regulatory mechanisms of AcrB and CpxR on the colistin susceptibility. Importantly, we found that exogenous supplement of citrate, α-ketoglutaric acid, and agmatine sulfate could synergistically enhance the bactericidal effect of colistin, indicating that these metabolites may serve as potential adjuvants for colistin therapy. These results provide a theoretical basis for finding potential new drug targets and adjuvants.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2165-0497
Relation: https://doaj.org/toc/2165-0497
DOI: 10.1128/spectrum.00530-23
Access URL: https://doaj.org/article/3e999161431b46848c0f741f2fe48fea
Accession Number: edsdoj.3e999161431b46848c0f741f2fe48fea
Database: Directory of Open Access Journals
More Details
ISSN:21650497
DOI:10.1128/spectrum.00530-23
Published in:Microbiology Spectrum
Language:English