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"Dooley, James"
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Natural quorum sensing inhibitors effectively downregulate gene expression of Pseudomonas aeruginosa virulence factors
At present, anti-virulence drugs are being considered as potential therapeutic alternatives and/or adjuvants to currently failing antibiotics. These drugs do not kill bacteria but inhibit virulence factors essential for establishing infection and pathogenesis through targeting non-essential metabolic pathways reducing the selective pressure to develop resistance. We investigated the effect of naturally isolated plant compounds on the repression of the quorum sensing (QS) system which is linked to virulence/pathogenicity in
Pseudomonas aeruginosa
. Our results show that
trans
-cinnamaldehyde (CA) and salicylic acid (SA) significantly inhibit expression of QS regulatory and virulence genes in
P. aeruginosa
PAO1 at sub-inhibitory levels without any bactericidal effect. CA effectively downregulated both the
las
and
rhl
QS systems with
lasI
and
lasR
levels inhibited by 13- and 7-fold respectively compared to 3- and 2-fold reductions with SA treatment, during the stationary growth phase. The QS inhibitors (QSI) also reduced the production of extracellular virulence factors with CA reducing protease, elastase and pyocyanin by 65%, 22% and 32%, respectively. The QSIs significantly reduced biofilm formation and concomitantly with repressed rhamnolipid gene expression, only trace amount of extracellular rhamnolipids were detected. The QSIs did not completely inhibit virulence factor expression and production but their administration significantly lowered the virulence phenotypes at both the transcriptional and extracellular levels. This study shows the significant inhibitory effect of natural plant-derived compounds on the repression of QS systems in
P. aeruginosa
.
Journal Article
Biofilm regulation in Clostridioides difficile: Novel systems linked to hypervirulence
Clostridiodes difficile ( C . difficile ) was ranked an “urgent threat” by the Centers for Disease Control and Prevention (CDC) in 2019. C . difficile infection (CDI) is the most common healthcare-associated infection (HAI) in the United States of America as well as the leading cause of antibiotic-associated gastrointestinal disease. C . difficile is a gram-positive, rod-shaped, spore-forming, anaerobic bacterium that causes infection of the epithelial lining of the gut. CDI occurs most commonly after disruption of the human gut microflora following the prolonged use of broad-spectrum antibiotics. However, the recurrent nature of this disease has led to the hypothesis that biofilm formation may play a role in its pathogenesis. Biofilms are sessile communities of bacteria protected from extracellular stresses by a matrix of self-produced proteins, polysaccharides, and extracellular DNA. Biofilm regulation in C . difficile is still incompletely understood, and its role in disease recurrence has yet to be fully elucidated. However, many factors have been found to influence biofilm formation in C . difficile , including motility, adhesion, and hydrophobicity of the bacterial cells. Small changes in one of these systems can greatly influence biofilm formation. Therefore, the biofilm regulatory system would need to coordinate all these systems to create optimal biofilm-forming physiology under appropriate environmental conditions. The coordination of these systems is complex and multifactorial, and any analysis must take into consideration the influences of the stress response, quorum sensing (QS), and gene regulation by second messenger molecule cyclic diguanosine monophosphate (c-di-GMP). However, the differences in biofilm-forming ability between C . difficile strains such as 630 and the “hypervirulent” strain, R20291, make it difficult to assign a “one size fits all” mechanism to biofilm regulation in C . difficile . This review seeks to consolidate published data regarding the regulation of C . difficile biofilms in order to identify gaps in knowledge and propose directions for future study.
Journal Article
Competent but complex communication: The phenomena of pheromone-responsive plasmids
Enterococci are robust gram-positive bacteria that are found in a variety of surroundings and that cause a significant number of healthcare-associated infections. The genus possesses a high-efficiency pheromone-responsive plasmid (PRP) transfer system for genetic exchange that allows antimicrobial-resistance determinants to spread within bacterial populations. The pCF10 plasmid system is the best characterised, and although other PRP systems are structurally similar, they lack exact functional homologues of pCF10-encoded genes. In this review, we provide an overview of the enterococcal PRP systems, incorporating functional details for the less-well-defined systems. We catalogue the virulence-associated elements of the PRPs that have been identified to date, and we argue that this reinforces the requirement for elucidation of the less studied systems.
Journal Article
Microbial Biosurfactants: Antimicrobial Activity and Potential Biomedical and Therapeutic Exploits
The rapid emergence of multidrug-resistant pathogens worldwide has raised concerns regarding the effectiveness of conventional antibiotics. This can be observed in ESKAPE pathogens, among others, whose multiple resistance mechanisms have led to a reduction in effective treatment options. Innovative strategies aimed at mitigating the incidence of antibiotic-resistant pathogens encompass the potential use of biosurfactants. These surface-active agents comprise a group of unique amphiphilic molecules of microbial origin that are capable of interacting with the lipidic components of microorganisms. Biosurfactant interactions with different surfaces can affect their hydrophobic properties and as a result, their ability to alter microorganisms’ adhesion abilities and consequent biofilm formation. Unlike synthetic surfactants, biosurfactants present low toxicity and high biodegradability and remain stable under temperature and pH extremes, making them potentially suitable for targeted use in medical and pharmaceutical applications. This review discusses the development of biosurfactants in biomedical and therapeutic uses as antimicrobial and antibiofilm agents, in addition to considering the potential synergistic effect of biosurfactants in combination with antibiotics. Furthermore, the anti-cancer and anti-viral potential of biosurfactants in relation to COVID-19 is also discussed.
Journal Article
ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease
Wilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase gene ATP7B. Estimates for WD population prevalence vary with 1 in 30,000 generally quoted. However, some genetic studies have reported much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD and the pathogenicity/penetrance of WD variants by determining the frequency of ATP7B variants in a genomic sequence database. A catalogue of WD-associated ATP7B variants was constructed, and then, frequency information for these was extracted from the gnomAD data set. Pathogenicity of variants was assessed by (a) comparing gnomAD allele frequencies against the number of reports for variants in the WD literature and (b) using variant effect prediction algorithms. 231 WD-associated ATP7B variants were identified in the gnomAD data set, giving an initial estimated population prevalence of around 1 in 2400. After exclusion of WD-associated ATP7B variants with predicted low penetrance, the revised estimate showed a prevalence of around 1 in 20,000, with higher rates in the Asian and Ashkenazi Jewish populations. Reanalysis of other recent genetic studies using our penetrance criteria also predicted lower population prevalences for WD in the UK and France than had been reported. Our results suggest that differences in variant penetrance can explain the discrepancy between reported epidemiological and genetic prevalences of WD. They also highlight the challenge in defining penetrance when assigning causality to some ATP7B variants.
Journal Article
Developmental 'awakening' of primary motor cortex to the sensory consequences of movement
Before primary motor cortex (M1) develops its motor functions, it functions like a somatosensory area. Here, by recording from neurons in the forelimb representation of M1 in postnatal day (P) 8–12 rats, we demonstrate a rapid shift in its sensory responses. At P8-10, M1 neurons respond overwhelmingly to feedback from sleep-related twitches of the forelimb, but the same neurons do not respond to wake-related movements. By P12, M1 neurons suddenly respond to wake movements, a transition that results from opening the sensory gate in the external cuneate nucleus. Also at P12, fewer M1 neurons respond to individual twitches, but the full complement of twitch-related feedback observed at P8 is unmasked through local disinhibition. Finally, through P12, M1 sensory responses originate in the deep thalamorecipient layers, not primary somatosensory cortex. These findings demonstrate that M1 initially establishes a sensory framework upon which its later-emerging role in motor control is built.
Journal Article
Pseudomonas aeruginosa PA80 is a cystic fibrosis isolate deficient in RhlRI quorum sensing
Pseudomonas aeruginosa
uses quorum sensing (QS) to modulate the expression of several virulence factors that enable it to establish severe infections. The QS system in
P. aeruginosa
is complex, intricate and is dominated by two main
N
-acyl-homoserine lactone circuits, LasRI and RhlRI. These two QS systems work in a hierarchical fashion with LasRI at the top, directly regulating RhlRI. Together these QS circuits regulate several virulence associated genes, metabolites, and enzymes in
P. aeruginosa
. Paradoxically, LasR mutants are frequently isolated from chronic
P. aeruginosa
infections, typically among cystic fibrosis (CF) patients. This suggests
P. aeruginosa
can undergo significant evolutionary pathoadaptation to persist in long term chronic infections. In contrast, mutations in the RhlRI system are less common. Here, we have isolated a clinical strain of
P. aeruginosa
from a CF patient that has deleted the transcriptional regulator RhlR entirely. Whole genome sequencing shows the
rhlR
locus is deleted in PA80 alongside a few non-synonymous mutations in virulence factors including protease
lasA
and rhamnolipid
rhlA, rhlB, rhlC.
Importantly we did not observe any mutations in the LasRI QS system. PA80 does not appear to have an accumulation of mutations typically associated with several hallmark pathoadaptive genes (i.e.,
mexT, mucA, algR, rpoN, exsS, ampR
). Whole genome comparisons show that
P. aeruginosa
strain PA80 is closely related to the hypervirulent Liverpool epidemic strain (LES) LESB58. PA80 also contains several genomic islands (GI’s) encoding virulence and/or resistance determinants homologous to LESB58. To further understand the effect of these mutations in PA80 QS regulatory and virulence associated genes, we compared transcriptional expression of genes and phenotypic effects with isogenic mutants in the genetic reference strain PAO1. In PAO1, we show that deletion of
rhlR
has a much more significant impact on the expression of a wide range of virulence associated factors rather than deletion of
lasR
. In PA80, no QS regulatory genes were expressed, which we attribute to the inactivation of the RhlRI QS system by deletion of
rhlR
and mutation of
rhlI.
This study demonstrates that inactivation of the LasRI system does not impact RhlRI regulated virulence factors. PA80 has bypassed the common pathoadaptive mutations observed in LasR by targeting the RhlRI system. This suggests that RhlRI is a significant target for the long-term persistence of
P. aeruginosa
in chronic CF patients. This raises important questions in targeting QS systems for therapeutic interventions.
Journal Article
Bacterivorous Ciliate Tetrahymena pyriformis Facilitates vanA Antibiotic Resistance Gene Transfer in Enterococcus faecalis
Background: Wastewater treatment plants (WWTPs) are hotspots for the emergence and spread of antibiotic resistance genes (ARGs). In activated sludge treatment systems, bacterivorous protozoa play a crucial role in biological processes, yet their impact on the horizontal gene transfer in Gram-positive enteric bacteria remains largely unexplored. This study investigated whether the ciliate Tetrahymena pyriformis facilitates the transfer of antibiotic resistance genes between Enterococcus faecalis strains. Methods: Conjugation assays were conducted under laboratory conditions using a vanA-carrying donor and a rifampicin-resistant recipient at an initial bacterial concentration of 109 CFU/mL and ciliate density of 105 N/mL. Results: Transconjugant numbers peaked at 2 h when experiments started with recipient bacteria harvested in the exponential growth phase, and at 24 h when bacteria were in the stationary phase. In both cases, vanA gene transfer frequency was highest at 24 h (10−4–10−5 CFU/mL), and the presence of energy sources increased gene transfer frequency by one order of magnitude. Conclusions: These findings suggest that ciliate grazing may contribute to vanA gene transfer in WWTP effluents, potentially facilitating its dissemination among permissive bacteria. Given the ecological and public health risks associated with vanA gene persistence in wastewater systems, understanding protozoan-mediated gene transfer is crucial for mitigating the spread of antibiotic resistance in aquatic environments.
Journal Article