PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional Level
ABSTRACT The two-component system (TCS) PhoPQ has been demonstrated to be crucial for the formation of resistance to quinolones and cephalosporins in Salmonella Enteritidis (S. Enteritidis). However, the mechanism underlying PhoPQ-mediated antibiotic resistance formation remains poorly understood. H...
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American Society for Microbiology
2023-06-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03395-22 |
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| author | Mengjun Hu Yuyan Zhang Xiaozhen Huang Mu He Jinyu Zhu Zengfeng Zhang Yan Cui Shoukui He Xianming Shi |
| author_facet | Mengjun Hu Yuyan Zhang Xiaozhen Huang Mu He Jinyu Zhu Zengfeng Zhang Yan Cui Shoukui He Xianming Shi |
| author_sort | Mengjun Hu |
| collection | DOAJ |
| description | ABSTRACT The two-component system (TCS) PhoPQ has been demonstrated to be crucial for the formation of resistance to quinolones and cephalosporins in Salmonella Enteritidis (S. Enteritidis). However, the mechanism underlying PhoPQ-mediated antibiotic resistance formation remains poorly understood. Here, it was shown that PhoP transcriptionally regulated an assortment of genes associated with envelope homeostasis, the osmotic stress response, and the redox balance to confer resistance to quinolones and cephalosporins in S. Enteritidis. Specifically, cells lacking the PhoP regulator, under nalidixic acid and ceftazidime stress, bore a severely compromised membrane on the aspects of integrity, fluidity, and permeability, with deficiency to withstand osmolarity stress, an increased accumulation of intracellular reactive oxygen species, and dysregulated redox homeostasis, which are unfavorable for bacterial survival. The phosphorylated PhoP elicited transcriptional alterations of resistance-associated genes, including the outer membrane porin ompF and the aconitate hydratase acnA, by directly binding to their promoters, leading to a limited influx of antibiotics and a well-maintained intracellular metabolism. Importantly, it was demonstrated that the cavity of the PhoQ sensor domain bound to and sensed quinolones/cephalosporins via the crucial surrounding residues, as their mutations abrogated the binding and PhoQ autophosphorylation. This recognition mode promoted signal transduction that activated PhoP, thereby modulating the transcription of downstream genes to accommodate cells to antibiotic stress. These findings have revealed how bacteria employ a specific TCS to sense antibiotics and combat them, suggesting PhoPQ as a potential drug target with which to surmount S. Enteritidis. IMPORTANCE The prevalence of quinolone and cephalosporin-resistant S. Enteritidis is of increasing clinical concern. Thus, it is imperative to identify novel therapeutic targets with which to treat S. Enteritidis-associated infections. The PhoPQ two-component system is conserved across a variety of Gram-negative pathogens, by which bacteria adapt to a range of environmental stimuli. Our earlier work has demonstrated the importance of PhoPQ in the resistance formation in S. Enteritidis to quinolones and cephalosporins. In the current work, we identified a global profile of genes that are regulated by PhoP under antibiotic stresses, with a focus on how PhoP regulated downstream genes, either positively or negatively. Additionally, we established that PhoQ sensed quinolones and cephalosporins in a manner of directly binding to them. These identified genes and pathways that are mediated by PhoPQ represent promising targets for the development of a drug potentiator with which to neutralize antibiotic resistance in S. Enteritidis. |
| first_indexed | 2024-03-13T03:01:03Z |
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| spelling | doaj.art-dd6889fd6ddd488c9b68f33eb92380ee2024-08-11T18:08:55ZengAmerican Society for MicrobiologymBio2150-75112023-06-0114310.1128/mbio.03395-22PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional LevelMengjun Hu0Yuyan Zhang1Xiaozhen Huang2Mu He3Jinyu Zhu4Zengfeng Zhang5Yan Cui6Shoukui He7Xianming Shi8Department of Food Science & Technology, School of Agriculture & Biology, and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Food Science & Technology, School of Agriculture & Biology, and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Food Science & Technology, School of Agriculture & Biology, and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Food Science & Technology, School of Agriculture & Biology, and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Food Science & Technology, School of Agriculture & Biology, and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Food Science & Technology, School of Agriculture & Biology, and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Food Science & Technology, School of Agriculture & Biology, and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Food Science & Technology, School of Agriculture & Biology, and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Food Science & Technology, School of Agriculture & Biology, and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, ChinaABSTRACT The two-component system (TCS) PhoPQ has been demonstrated to be crucial for the formation of resistance to quinolones and cephalosporins in Salmonella Enteritidis (S. Enteritidis). However, the mechanism underlying PhoPQ-mediated antibiotic resistance formation remains poorly understood. Here, it was shown that PhoP transcriptionally regulated an assortment of genes associated with envelope homeostasis, the osmotic stress response, and the redox balance to confer resistance to quinolones and cephalosporins in S. Enteritidis. Specifically, cells lacking the PhoP regulator, under nalidixic acid and ceftazidime stress, bore a severely compromised membrane on the aspects of integrity, fluidity, and permeability, with deficiency to withstand osmolarity stress, an increased accumulation of intracellular reactive oxygen species, and dysregulated redox homeostasis, which are unfavorable for bacterial survival. The phosphorylated PhoP elicited transcriptional alterations of resistance-associated genes, including the outer membrane porin ompF and the aconitate hydratase acnA, by directly binding to their promoters, leading to a limited influx of antibiotics and a well-maintained intracellular metabolism. Importantly, it was demonstrated that the cavity of the PhoQ sensor domain bound to and sensed quinolones/cephalosporins via the crucial surrounding residues, as their mutations abrogated the binding and PhoQ autophosphorylation. This recognition mode promoted signal transduction that activated PhoP, thereby modulating the transcription of downstream genes to accommodate cells to antibiotic stress. These findings have revealed how bacteria employ a specific TCS to sense antibiotics and combat them, suggesting PhoPQ as a potential drug target with which to surmount S. Enteritidis. IMPORTANCE The prevalence of quinolone and cephalosporin-resistant S. Enteritidis is of increasing clinical concern. Thus, it is imperative to identify novel therapeutic targets with which to treat S. Enteritidis-associated infections. The PhoPQ two-component system is conserved across a variety of Gram-negative pathogens, by which bacteria adapt to a range of environmental stimuli. Our earlier work has demonstrated the importance of PhoPQ in the resistance formation in S. Enteritidis to quinolones and cephalosporins. In the current work, we identified a global profile of genes that are regulated by PhoP under antibiotic stresses, with a focus on how PhoP regulated downstream genes, either positively or negatively. Additionally, we established that PhoQ sensed quinolones and cephalosporins in a manner of directly binding to them. These identified genes and pathways that are mediated by PhoPQ represent promising targets for the development of a drug potentiator with which to neutralize antibiotic resistance in S. Enteritidis.https://journals.asm.org/doi/10.1128/mbio.03395-22two-component systemPhoPQantibiotic resistancetranscriptional regulationantibiotic recognition |
| spellingShingle | Mengjun Hu Yuyan Zhang Xiaozhen Huang Mu He Jinyu Zhu Zengfeng Zhang Yan Cui Shoukui He Xianming Shi PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional Level mBio two-component system PhoPQ antibiotic resistance transcriptional regulation antibiotic recognition |
| title | PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional Level |
| title_full | PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional Level |
| title_fullStr | PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional Level |
| title_full_unstemmed | PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional Level |
| title_short | PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional Level |
| title_sort | phopq regulates quinolone and cephalosporin resistance formation in salmonella enteritidis at the transcriptional level |
| topic | two-component system PhoPQ antibiotic resistance transcriptional regulation antibiotic recognition |
| url | https://journals.asm.org/doi/10.1128/mbio.03395-22 |
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