In vivo Host Environment Alters Pseudomonas aeruginosa Susceptibility to Aminoglycoside Antibiotics

Pan, Xiaolei; Dong, Yuanyuan; Fan, Zheng; Liu, Chang; Xia, Bing; Shi, Jing; Bai, Fang; Jin, Yongxin; Cheng, Zhihui; Jin, Shouguang; Wu, Weihui

doi:10.3389/fcimb.2017.00083

Cited by 13 publications

(9 citation statements)

References 56 publications

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“…Fourthly, oxidative stress induces efflux pump gene expression, promoting aminoglycoside tolerance [62]. Excessive ROS production has also been reported to lead to a reduced membrane potential and modification of LPS, which potentiates tobramycin activity [63].…”

Section: Mediators Of the Immune Responsementioning

confidence: 99%

The cystic fibrosis lung microenvironment alters antibiotic activity: causes and effects

et al. 2021

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Chronic airway colonisation by Pseudomonas aeruginosa, a hallmark of cystic fibrosis (CF) lung disease, is associated with increased morbidity and mortality and despite aggressive antibiotic treatment, P. aeruginosa is able to persist in CF airways. In vitro antibiotic susceptibility assays are poor predictors of antibiotic efficacy to treat respiratory tract infections in the CF patient population and the selection of the antibiotic(s) is often made on an empirical base. In the current review, we discuss the factors that are responsible for the discrepancies between antibiotic activity in vitro and clinical efficacy in vivo. We describe how the CF lung microenvironment, shaped by host factors (such as iron, mucus, immune mediators and oxygen availability) and the microbiota, influences antibiotic activity and varies widely between patients. A better understanding of the CF microenvironment and population diversity may thus help improve in vitro antibiotic susceptibility testing and clinical decision making, in turn increasing the success rate of antibiotic treatment.

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Section: Mediators Of the Immune Responsementioning

confidence: 99%

The cystic fibrosis lung microenvironment alters antibiotic activity: causes and effects

et al. 2021

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“…Indeed, these studies denote that some antimicrobial agents are effective in vitro but not in vivo or vice versa. We and others previously demonstrated that lung epithelial cells modulate the activity of antibiotics in vitro [15–19]. In particular, culturing biofilms of Pseudomonas aeruginosa on the surface of in vivo -like three-dimensional (3-D) lung epithelial cells enhanced the activity of aminoglycosides as compared to when these same biofilms were cultured on a plastic surface [19].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, Wu et al recently demonstrated that P . aeruginosa isolated directly from mouse lungs was more susceptible to aminoglycosides as compared to laboratory-grown cultures, suggesting that host factors influence antibiotic activity in vivo [15]. In the present study we aimed at elucidating (i) whether the host microenvironment influences aminoglycoside activity against bacterial pathogens, (ii) if host metabolites can potentiate aminoglycoside activity, and (iii) what the underlying mode of action is.…”

Section: Introductionmentioning

confidence: 99%

Host metabolites stimulate the bacterial proton motive force to enhance the activity of aminoglycoside antibiotics

et al. 2019

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Antibiotic susceptibility of bacterial pathogens is typically evaluated using in vitro assays that do not consider the complex host microenvironment. This may help explaining a significant discrepancy between antibiotic efficacy in vitro and in vivo , with some antibiotics being effective in vitro but not in vivo or vice versa. Nevertheless, it is well-known that antibiotic susceptibility of bacteria is driven by environmental factors. Lung epithelial cells enhance the activity of aminoglycoside antibiotics against the opportunistic pathogen Pseudomonas aeruginosa , yet the mechanism behind is unknown. The present study addresses this gap and provides mechanistic understanding on how lung epithelial cells stimulate aminoglycoside activity. To investigate the influence of the local host microenvironment on antibiotic activity, an in vivo -like three-dimensional (3-D) lung epithelial cell model was used. We report that conditioned medium of 3-D lung cells, containing secreted but not cellular components, potentiated the bactericidal activity of aminoglycosides against P . aeruginosa , including resistant clinical isolates, and several other pathogens. In contrast, conditioned medium obtained from the same cell type, but grown as conventional (2-D) monolayers did not influence antibiotic efficacy. We found that 3-D lung cells secreted endogenous metabolites (including succinate and glutamate) that enhanced aminoglycoside activity, and provide evidence that bacterial pyruvate metabolism is linked to the observed potentiation of antimicrobial activity. Biochemical and phenotypic assays indicated that 3-D cell conditioned medium stimulated the proton motive force (PMF), resulting in increased bacterial intracellular pH. The latter stimulated antibiotic uptake, as determined using fluorescently labelled tobramycin in combination with flow cytometry analysis. Our findings reveal a cross-talk between host and bacterial metabolic pathways, that influence downstream activity of antibiotics. Understanding the underlying basis of the discrepancy between the activity of antibiotics in vitro and in vivo may lead to improved diagnostic approaches and pave the way towards novel means to stimulate antibiotic activity.

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“…It is possible that V. parahaemolyticus uses similar mechanisms to establish colonization in the intestine of the host. Alternatively, the hostile environment in C. elegans may decrease the membrane potential of V. parahaemolyticus as observed in Pseudomonas aeruginosa 50 . If so, bacteria may upregulate the expression of genes involved in TCA cycle and ETC as a feedback to compensate the decrease in ATP production.…”

Section: Resultsmentioning

confidence: 99%

Organism dual RNA‐seq reveals the importance of BarA/UvrY inVibrio parahaemolyticusvirulence

Zhang¹,

Xie²,

Zhang³

et al. 2020

FASEB j.

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Elucidation of host‐pathogen interaction is essential for developing effective strategies to combat bacterial infection. Dual RNA‐Seq using cultured cells or tissues/organs as the host of pathogen has emerged as a novel strategy to understand the responses concurrently from both pathogen and host at cellular level. However, bacterial infection mostly causes systematic responses from the host at organism level where the interplay is urgently to be understood but inevitably being neglected by the current practice. Here, we developed an approach that simultaneously monitor the genome‐wide infection‐linked transcriptional alterations in both pathogenic Vibrio parahaemolyticus and the infection host nematode Caenorhabditis elegans. Besides the dynamic alterations in transcriptomes of both C. elegans and V. parahaemolyticus during infection, we identify a two‐component system, BarA/UvrY, that is important for virulence in host. BarA/UvrY not only controls the virulence factors in V. parahaemolyticus including Type III and Type VI secretion systems, but also attenuates innate immune responses in C. elegans, including repression on the MAP kinase‐mediated cascades. Thus, our study exemplifies the use of dual RNA‐Seq at organism level to uncover previously unrecognized interplay between host and pathogen.

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In vivo Host Environment Alters Pseudomonas aeruginosa Susceptibility to Aminoglycoside Antibiotics

Cited by 13 publications

References 56 publications

The cystic fibrosis lung microenvironment alters antibiotic activity: causes and effects

The cystic fibrosis lung microenvironment alters antibiotic activity: causes and effects

Host metabolites stimulate the bacterial proton motive force to enhance the activity of aminoglycoside antibiotics

Organism dual RNA‐seq reveals the importance of BarA/UvrY inVibrio parahaemolyticusvirulence

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