Cinnamaldehyde Induces Expression of Efflux Pumps and Multidrug Resistance in Pseudomonas aeruginosa

Tetard, Alexandre; Zedet, Andy; Girard, Christian; Plésiat, Patrick; Llanes, Catherine

doi:10.1128/aac.01081-19

Cited by 30 publications

(32 citation statements)

References 55 publications

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“…We observed the induction of genes encoding the MexCD-OprJ, MexEF-OprN, and MexKJ efflux pumps and recovered a transposon mutant with a defect in MexAB-OprM. A similar upregulation of the mexB, mexC, mexE, and mexY genes was recently reported by Tetard et al (43) in P. aeruginosa PA14 treated with cinnamaldehyde. Interestingly, the induction of efflux pump transporters and chaperones was also observed in P. putida exposed to toluene (44), thus suggesting that the response to p-anisaldehyde represents part of a broader strategy used by P. aeruginosa to cope with solvent stress.…”

Section: Discussionsupporting

confidence: 86%

Antimicrobial Activity of, and Cellular Pathways Targeted by, p -Anisaldehyde and Epigallocatechin Gallate in the Opportunistic Human Pathogen Pseudomonas aeruginosa

Adewunmi

Namjilsuren

Walker

et al. 2020

Appl Environ Microbiol

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Plant-derived aldehydes are constituents of essential oils that possess broad-spectrum antimicrobial activity and kill microorganisms without promoting resistance. In our previous study, we incorporated p-anisaldehyde from star anise into a polymer network called proantimicrobial networks via degradable acetals (PANDAs) and used it as a novel drug delivery platform. PANDAs released p-anisaldehyde upon a change in pH and humidity and controlled the growth of the multidrug-resistant pathogen Pseudomonas aeruginosa PAO1. In this study, we identified the cellular pathways targeted by p-anisaldehyde by generating 10,000 transposon mutants of PAO1 and screened them for hypersensitivity to p-anisaldehyde. To improve the antimicrobial efficacy of p-anisaldehyde, we combined it with epigallocatechin gallate (EGCG), a polyphenol from green tea, and demonstrated that it acts synergistically with p-anisaldehyde in killing P. aeruginosa. We then used transcriptome sequencing to profile the responses of P. aeruginosa to p-anisaldehyde, EGCG, and their combination. The exposure to p-anisaldehyde altered the expression of genes involved in modification of the cell envelope, membrane transport, drug efflux, energy metabolism, molybdenum cofactor biosynthesis, and the stress response. We also demonstrate that the addition of EGCG reversed many p-anisaldehyde-coping effects and induced oxidative stress. Our results provide insight into the antimicrobial activity of p-anisaldehyde and its interactions with EGCG and may aid in the rational identification of new synergistically acting combinations of plant metabolites. Our study also confirms the utility of the thiol-ene polymer platform for the sustained and effective delivery of hydrophobic and volatile antimicrobial compounds. IMPORTANCE Essential oils (EOs) are plant-derived products that have long been exploited for their antimicrobial activities in medicine, agriculture, and food preservation. EOs represent a promising alternative to conventional antibiotics due to their broad-range antimicrobial activity, low toxicity to human commensal bacteria, and capacity to kill microorganisms without promoting resistance. Despite the progress in the understanding of the biological activity of EOs, our understanding of many aspects of their mode of action remains inconclusive. The overarching aim of this work was to address these gaps by studying the molecular interactions between an antimicrobial plant aldehyde and the opportunistic human pathogen Pseudomonas aeruginosa. The results of this study identify the microbial genes and associated pathways involved in the response to antimicrobial phytoaldehydes and provide insights into the molecular mechanisms governing the synergistic effects of individual constituents within essential oils.

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Section: Discussionsupporting

confidence: 86%

Antimicrobial Activity of, and Cellular Pathways Targeted by, p -Anisaldehyde and Epigallocatechin Gallate in the Opportunistic Human Pathogen Pseudomonas aeruginosa

Adewunmi

Namjilsuren

Walker

et al. 2020

Appl Environ Microbiol

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“…Indeed some papers report an increase of susceptibility to antibiotics after treatment with essential oils 25,26 . Although a pletora of publications did not show development of resistance to EOs, a very recent publication suggested the induction of efflux pumps and multidrug resistance in P. aeruginosa by Cinnamaldehyde, the main component of cinnamon 27 . Therefore, in light of the recent reports, much still needs to be clarified on the effect of essential oils on bacterial multi-drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Essential oils against bacterial isolates from cystic fibrosis patients by means of antimicrobial and unsupervised machine learning approaches

Ragno

Papa²,

Patsilinakos

et al. 2020

Sci Rep

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Recurrent and chronic respiratory tract infections in cystic fibrosis (CF) patients result in progressive lung damage and represent the primary cause of morbidity and mortality. Staphylococcus aureus (S. aureus) is one of the earliest bacteria in CF infants and children. Starting from early adolescence, patients become chronically infected with Gram-negative non-fermenting bacteria, and Pseudomonas aeruginosa (P. aeruginosa) is the most relevant and recurring. Intensive use of antimicrobial drugs to fight lung infections inevitably leads to the onset of antibiotic resistant bacterial strains. New antimicrobial compounds should be identified to overcome antibiotic resistance in these patients. Recently interesting data were reported in literature on the use of natural derived compounds that inhibited in vitro S. aureus and P. aeruginosa bacterial growth. Essential oils, among these, seemed to be the most promising. In this work is reported an extensive study on 61 essential oils (EOs) against a panel of 40 clinical strains isolated from CF patients. To reduce the in vitro procedure and render the investigation as convergent as possible, machine learning clusterization algorithms were firstly applied to pickup a fewer number of representative strains among the panel of 40. This approach allowed us to easily identify three EOs able to strongly inhibit bacterial growth of all bacterial strains. Interestingly, the EOs antibacterial activity is completely unrelated to the antibiotic resistance profile of each strain. Taking into account the results obtained, a clinical use of EOs could be suggested. Cystic fibrosis (CF), one of the most common lethal genetic disorders in Caucasian population, is inherited as an autosomal recessive disease and affects 70.000 persons worldwide (Cystic Fibrosis Foundation, CFF). The defective gene, identified in 1989, is the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) that is carried by 4% of persons (among Caucasians). Since CFTR encodes for a chloride channel of the epithelial cell surface, CF patients manifest a variety of multi-organ problems due to the alteration of sodium and chloride secretion across cell membranes and the subsequent luminal dehydration 1. The impairment of mucociliary clearance, which should remove all microbes entering the airways, leads to the production of a thick and dehydrated mucus in the CF lung, which promotes the airway chronic bacterial colonization 2. The microbiology of CF respiratory tract is peculiar. In the early stage of life, it is characterized by the prevalence of the Gram-positive bacterium Staphylococcus aureus (S. aureus). Overall, in 2017 more than half of affected individuals had at least one culture positive for methicillin sensitive S. aureus (MSSA). The highest prevalence of methicillin resistant S. aureus (MRSA) occurs in individuals between the ages of 10 and 30, while MSSA reaches the peak among patients younger than 10 (Cystic Fibrosis Foundation. 2017. Patient Registry Annual

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“…Studies on laboratory-adapted biocide insensitive P. aeruginosa indicated a correlation with antimicrobial resistance with efflux pump overexpression as the main mechanism of resistance [17,24,[66][67][68] and reviewed in [43,69]. These observations have led to the hypothesis that there could be a correlation between biocide use and the development of antimicrobial resistance in clinical or environmental situations, although this has never been translated from laboratory-adapted strains to a confirmation in the natural environment.…”

Section: Discussionmentioning

confidence: 99%

Efflux Pump-Driven Antibiotic and Biocide Cross-Resistance in Pseudomonas aeruginosa Isolated from Different Ecological Niches: A Case Study in the Development of Multidrug Resistance in Environmental Hotspots

et al. 2020

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Pseudomonas aeruginosa is an opportunistic pathogen displaying high intrinsic antimicrobial resistance and the ability to thrive in different ecological environments. In this study, the ability of P. aeruginosa to develop simultaneous resistance to multiple antibiotics and disinfectants in different natural niches were investigated using strains collected from clinical samples, veterinary samples, and wastewater. The correlation between biocide and antimicrobial resistance was determined by employing principal component analysis. Molecular mechanisms linking biocide and antimicrobial resistance were interrogated by determining gene expression using RT-qPCR and identifying a potential genetic determinant for co- and cross-resistance using whole-genome sequencing. A subpopulation of P. aeruginosa isolates belonging to three sequence types was resistant against the common preservative benzalkonium chloride and showed cross-resistance to fluoroquinolones, cephalosporins, aminoglycosides, and multidrug resistance. Of these, the epidemiological high-risk ST235 clone was the most abundant. The overexpression of the MexAB-OprM drug efflux pump resulting from amino acid mutations in regulators MexR, NalC, or NalD was the major contributing factor for cross-resistance that could be reversed by an efflux pump inhibitor. This is the first comparison of antibiotic-biocide cross-resistance in samples isolated from different ecological niches and serves as a confirmation of laboratory-based studies on biocide adapted isolates. The isolates from wastewater had a higher incidence of multidrug resistance and biocide-antibiotic cross-resistance than those from clinical and veterinary settings.

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Cinnamaldehyde Induces Expression of Efflux Pumps and Multidrug Resistance in Pseudomonas aeruginosa

Cited by 30 publications

References 55 publications

Antimicrobial Activity of, and Cellular Pathways Targeted by, p -Anisaldehyde and Epigallocatechin Gallate in the Opportunistic Human Pathogen Pseudomonas aeruginosa

Antimicrobial Activity of, and Cellular Pathways Targeted by, p -Anisaldehyde and Epigallocatechin Gallate in the Opportunistic Human Pathogen Pseudomonas aeruginosa

Essential oils against bacterial isolates from cystic fibrosis patients by means of antimicrobial and unsupervised machine learning approaches

Efflux Pump-Driven Antibiotic and Biocide Cross-Resistance in Pseudomonas aeruginosa Isolated from Different Ecological Niches: A Case Study in the Development of Multidrug Resistance in Environmental Hotspots

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