In-depth proteomic analyzing the activated effect and sensitized mechanism of clinical multi-drug resistant of Pseudomonas aeruginosa by TanReQing injection
Ontology highlight
ABSTRACT:
ORGANISM(S): Pseudomonas Aeruginosa Aes-1r
SUBMITTER: 
Xianyu Li
PROVIDER: PXD039911 | iProX | Tue Feb 07 00:00:00 GMT 2023
REPOSITORIES: iProX
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Project description:Pseudomonas aeruginosa (PA) is an opportunistic human pathogen, causing serious chronic infections. PA can adapt efficiently to antibiotic stressors via different genotypic or phenotypic strategies such as resistance and tolerance. The adaptation regulatory system is not always very well understood. In this study, we use shotgun proteomics to investigate the system-level response to tobramycin in two clinical wound PA isolates and PAO1. We profiled each strain for its antibiotic drug-tolerant phenotype using supra-minimum inhibitory concentrations (supra-MIC) of tobramycin and apply proteomics to investigate the protein expression profiles. The MIC revealed that all isolates were susceptible to tobramycin but at supra-MIC concentrations at stationary growth, a degree of tolerance was observed for the isolates. We identified around 40 % of the total proteins encoded by the PA genome and highlighted shared and unique protein signatures for all isolates. Comparative proteome profiling in the absence of antibiotic treatment showed divergent fingerprints, despite similarities in the growth behavior of the isolates. In the presence of tobramycin, the isolates shared a common response in the downregulation of proteins involved in the two-component system, whereas stress response proteins were present at higher levels. Our findings provide insight into the use of proteomic tools to dissect the system-level response in clinical isolates in the absence and presence of antibiotic stress.
2024-10-17 | PXD051528 | Pride
Project description:Aim: Colistin is the only effective antibiotic in some cases of Pseudo monas aeruginosa resistance to all tested antibiotics, even carbapenem. On the other hand, biofilm formation is one of the antibiotic resistance mechanisms in this bacterium. The aim of this study was to examine biofilm formation in colistin-resistant P. aeruginosa for the first time. Method: Two groups of P. aeruginosa were included in this study: 1) colistin-resistant and 2) colistin-susceptible. Biofilm formation was determined in these groups using the micro-tube test well as PCR to detect the genes involved in biofilm formation (ppk and molA). The plasmids for colistin resistance, mcr-1 and mcr-2, were also determined. P. aeruginosa ATCC 27853 was used as a control for all tests. Results: Strong biofilm formation was observed only in colistin-susceptible strains, and ppk and modA were not detected in colistin-resistant strains. The control strain P. aeruginosa ATCC 27853 possesses ppk and modA and is categorized as a strong biofilm formation group. According to the results of this study, colistin resistance is associated with defective biofilm formation, as reported by other studies on Acinetobacter baumannii.
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Project description:Antibiotic resistance is one of the most pressing threats to human health, yet recent work highlights how loss of resistance may also drive pathogenesis in some bacteria. In two recent studies, we found that in vitro beta-lactam antibiotic and nutrient stresses faced during infection selected for the genetic inactivation of the Pseudomonas aeruginosa (Pa) antibiotic efflux pump mexEFoprN. Unexpectedly, efflux pump mutations increased Pa virulence during infection; however, neither the prevalence of efflux pump inactivating mutations in real human infections, nor the mechanisms driving increased virulence of efflux pump mutants were known. We hypothesized that human infection would select for efflux pump mutations that drive increased virulence in Pa clinical isolates. Using genome sequencing of hundreds of Pa clinical isolates, we show that mexEFoprN efflux pump inactivating mutations are enriched in Pa cystic fibrosis isolates relative to Pa intensive care unit clinical isolates. Combining RNA-seq, metabolomics, genetic approaches, and infection models we show that efflux pump mutants increase expression of two key Pa virulence factors, elastase and rhamnolipids, which increased Pa virulence and lung damage during both acute and chronic infections. We show that increased virulence factor production was driven by increased Pseudomonas quinolone signal levels, and this mechanism of increased virulence held true in both a representative ICU clinical isolate and the notorious CF Pa Liverpool epidemic strain. Together, our findings suggest that mutations inactivating antibiotic resistance mechanisms could increase patient mortality and morbidity.
2024-11-12 | MSV000096391 | MassIVE
Project description:Experimentally evolved PA population
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Project description:Gene Expression analysis of PA 3880 mutant
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Project description:ImportanceEvaluation of the microbiological diagnostic profile of multidrug-resistant Pseudomonas aeruginosa keratitis and potential management with rose bengal-photodynamic antimicrobial therapy (RB-PDAT) is important.ObjectiveTo document the disease progression of carbapenemase-resistant P aeruginosa keratitis after an artificial tear contamination outbreak.Design, setting, and participantsThis retrospective observation case series included 9 patients 40 years or older who presented at Bascom Palmer Eye Institute and had positive test results for multidrug-resistant P aeruginosa keratitis between January 1, 2022, and October 31, 2023.Main outcomes and measuresEvaluation of type III secretion phenotype, carbapenemase-resistance genes blaGES and blaVIM susceptibility to antibiotics, and in vitro and in vivo outcomes of RB-PDAT against multidrug-resistant P aeruginosa keratitis.ResultsAmong the 9 patients included in the analysis (5 women and 4 men; mean [SD] age, 73.4 [14.0] years), all samples tested positive for exoU and carbapenemase-resistant blaVIM and blaGES genes. Additionally, isolates were resistant to carbapenems as indicated by minimum inhibitory concentration testing. In vitro efficacy of RB-PDAT indicated its potential application for treating recalcitrant cases. These cases highlight the rapid progression and challenging management of multidrug-resistant P aeruginosa. Two patients were treated with RB-PDAT as an adjuvant to antibiotic therapy and had improved visual outcomes.Conclusions and relevanceThis case series highlights the concerning progression in resistance and virulence of P aeruginosa and emphasizes the need to explore alternative therapies like RB-PDAT that have broad coverage and no known antibiotic resistance. The findings support further investigation into the potential effects of RB-PDAT for other multidrug-resistant microbes.
| S-EPMC10958388 | biostudies-literature
Project description:BackgroundThe biofilm state of pathogens facilitates antimicrobial resistance which makes difficult-to-treat infections. In this regard, it has been found that the compounds screened from plant extracts represent one category of the most promising antibiofilm agents. However, the antibiofilm activities and the active ingredients of plant extracts remain largely unexplored. In this background, the study is (1) to screen out the plant extracts with antibiofilm ability against Pseudomonas aeruginosa, and (2) to identify the active ingredients in the plant extracts and elucidate the underlying mechanism of the antibiofilm activities.MethodsMicro-broth dilution method, in vitro biofilm model, LC-MS/MS analysis and P. aeruginosa-mouse infection model were adopted to assess the antibiofilm activity. GC-MS analysis was performed to detect the active ingredients in plasma. RNA-Seq, GO analysis, KEGG analysis and RT-qPCR were adopted to elucidate the underlying mechanism of antibiofilm activities against P. aeruginosa.ResultsLonicerae Japonicae Flos (LJF) among 13 plants could exert significant inhibitory effects on bacterial biofilm formation, mobility and toxin release in vitro, and it could exert antibiofilm effect in vivo too. Moreover, quinic acid, as one metabolite of chlorogenic acid, was found as an active ingredient in LJF against the biofilm of P. aeruginosa. The active ingredient significantly inhibited EPS secretion in biofilm formation and maturity and could achieve synergistic antibiofilm effect with levofloxacin. It reduced the biofilm formation by regulating core targets in quorum sensing system. In GO process, it was found that the core targets were significantly enriched in multiple biological processes involving locomotion, chemotaxis and motility mediated by flagellum/cilium, which was related to KEGG pathways such as bacterial chemotaxis, oxidative phosphorylation, ribosome, biofilm formation, cyanoamino acid metabolism and quorum sensing. Finally, the binding of quinic acid with core targets rhlA, rhlR and rhlB were validated by molecular docking and RT-qPCR.ConclusionsIn summary, the study verified the in vitro and in vivo antibiofilm effects of LJF against P. aeruginosa and elucidated the active ingredients in LJF and its conceivable pharmacological mechanism, indicating that quinic acid could have the potential of an antibiofilm agent against P. aeruginosa and related infections.
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Project description:We gathered the proteomic profile of 202 clinical P. aeruginosa isolates derived from a cystic fibrosis lung under planktonic growth conditions. Firstly, a comprehensive transcript/protein correlation across 174 clinical isolates at the same growth stage was performed allowing a characterization of proteins with long and short lifetimes. Consistent with the results from previous studies, proteins of the translational machinery and the key Quorum sensing mediators RpoS, Vfr, RhlR and MvfR were characterized as short-lived proteins. Again, no biochemical metric could explain differences between protein lifetimes further demonstrating a potentially undervalued importance of post-transcriptional regulation.
Secondly, a comparative multi-omics analysis was performed that highlighted the capacity to unearth novel characteristics for both antibiotic resistance and virulence traits. Investigating various tobramycin resistance mechanisms, the efflux pump system MexXY-OprM was determined as a key contributor of aminoglycoside modifying enzyme-driven resistance. MexY protein abundance was furthermore found to be directly regulated by the negative regulator MexZ. In tobramycin resistant isolates, the MexZ regulator was frequently identified as mutated or completely absent due to a possibly unidentified mechanism. This work found novel possible bacterial virulence factors by statistically comparing quantitative data and phenotypic survival data from a Galleria mellonella infection model. Additionally, a Random forest machine learning model was applied. The predictors with the highest predictive importance for the phenotypes of swarming motility, various antibiotic resistance phenotypes, and virulence were listed and discussed.
2023-02-23 | MSV000091351 | MassIVE