Antibiotic resistance alters the ability of to invade bacteria from the respiratory microbiome.

The emergence and spread of antibiotic resistance in bacterial pathogens is a global health threat. One important unanswered question is how antibiotic resistance influences the ability of a pathogen to invade the host-associated microbiome. Here we investigate how antibiotic resistance impacts the ability of a bacterial pathogen to invade bacteria from the microbiome, using the opportunistic bacterial pathogen and the respiratory microbiome as our model system.

Warming alters life-history traits and competition in a phage community.

Host-parasite interactions are highly susceptible to changes in temperature due to mismatches in species thermal responses. In nature, parasites often exist in communities, and responses to temperature are expected to vary between host-parasite pairs. Temperature change thus has consequences for both host-parasite dynamics and parasite-parasite interactions.

Plasmid-mediated phenotypic noise leads to transient antibiotic resistance in bacteria.

The rise of antibiotic resistance is a critical public health concern, requiring an understanding of mechanisms that enable bacteria to tolerate antimicrobial agents. Bacteria use diverse strategies, including the amplification of drug-resistance genes. In this paper, we showed that multicopy plasmids, often carrying antibiotic resistance genes in clinical bacteria, can rapidly amplify genes, leading to plasmid-mediated phenotypic noise and transient antibiotic resistance.

Interkingdom interactions between Pseudomonas aeruginosa and Candida albicans affect clinical outcomes and antimicrobial responses.

Infections that involve interkingdom microbial communities, such as those between bacteria and yeast pathogens, are difficult to treat, associated with worse patient outcomes, and may be a source of antimicrobial resistance. In this review, we address co-occurrence and co-infections of Candida albicans and Pseudomonas aeruginosa, two pathogens that occupy multiple infection niches in the human body, especially in immunocompromised patients. The interaction between the pathogen species influences microbe-host interactions, the effectiveness of antimicrobials and even infection outcomes, and may thus require adapted treatment strategies.

Reconstruction and Validation of Arterial Geometries for Computational Fluid Dynamics Using Multiple Temporal Frames of 4D Flow-MRI Magnitude Images.

Purpose: Segmentation and reconstruction of arterial blood vessels is a fundamental step in the translation of computational fluid dynamics (CFD) to the clinical practice. Four-dimensional flow magnetic resonance imaging (4D Flow-MRI) can provide detailed information of blood flow but processing this information to elucidate the underlying anatomical structures is challenging. In this study, we present a novel approach to create high-contrast anatomical images from retrospective 4D Flow-MRI data.

Mixed strain pathogen populations accelerate the evolution of antibiotic resistance in patients.

Antibiotic resistance poses a global health threat, but the within-host drivers of resistance remain poorly understood. Pathogen populations are often assumed to be clonal within hosts, and resistance is thought to emerge due to selection for de novo variants. Here we show that mixed strain populations are common in the opportunistic pathogen P.

Restriction-modification systems have shaped the evolution and distribution of plasmids across bacteria.

Many novel traits such as antibiotic resistance are spread by plasmids between species. Yet plasmids have different host ranges. Restriction-modification systems (R-M systems) are by far the most abundant bacterial defense system and therefore represent one of the key barriers to plasmid spread.

Calibration of patient-specific boundary conditions for coupled CFD models of the aorta derived from 4D Flow-MRI.

Patient-specific computational fluid dynamics (CFD) models permit analysis of complex intra-aortic hemodynamics in patients with aortic dissection (AD), where vessel morphology and disease severity are highly individualized. The simulated blood flow regime within these models is sensitive to the prescribed boundary conditions (BCs), so accurate BC selection is fundamental to achieve clinically relevant results. This study presents a novel reduced-order computational framework for the iterative flow-based calibration of 3-Element Windkessel Model (3EWM) parameters to generate patient-specific BCs.

The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence.

Antimicrobial peptides (AMPs) offer a promising solution to the antibiotic resistance crisis. However, an unresolved serious concern is that the evolution of resistance to therapeutic AMPs may generate cross-resistance to host AMPs, compromising a cornerstone of the innate immune response. We systematically tested this hypothesis using globally disseminated mobile colistin resistance (MCR) that has been selected by the use of colistin in agriculture and medicine.

Off-Target Integron Activity Leads to Rapid Plasmid Compensatory Evolution in Response to Antibiotic Selection Pressure.

Integrons are mobile genetic elements that have played an important role in the dissemination of antibiotic resistance. Under stress, the integron can generate combinatorial variation in resistance cassette expression by cassette reshuffling, accelerating the evolution of resistance. However, the flexibility of the integron integrase site recognition motif hints at potential off-target effects of the integrase on the rest of the genome that may have important evolutionary consequences.

Gut to lung translocation and antibiotic mediated selection shape the dynamics of Pseudomonas aeruginosa in an ICU patient.

Bacteria have the potential to translocate between sites in the human body, but the dynamics and consequences of within-host bacterial migration remain poorly understood. Here we investigate the link between gut and lung Pseudomonas aeruginosa populations in an intensively sampled ICU patient using a combination of genomics, isolate phenotyping, host immunity profiling, and clinical data. Crucially, we show that lung colonization in the ICU was driven by the translocation of P.

Pre-existing chromosomal polymorphisms in pathogenic potentiate the evolution of resistance to a last-resort antibiotic.

Bacterial pathogens show high levels of chromosomal genetic diversity, but the influence of this diversity on the evolution of antibiotic resistance by plasmid acquisition remains unclear. Here, we address this problem in the context of colistin, a 'last line of defence' antibiotic. Using experimental evolution, we show that a plasmid carrying the MCR-1 colistin resistance gene dramatically increases the ability of to evolve high-level colistin resistance by acquiring mutations in , an essential chromosomal gene involved in lipopolysaccharide biosynthesis.

Localized pmrB hypermutation drives the evolution of colistin heteroresistance.

Colistin has emerged as an important last line of defense for the treatment of infections caused by antibiotic-resistant gram-negative pathogens, but colistin resistance remains poorly understood. Here, we investigate the responses of ≈1,000 populations of a multi-drug-resistant (MDR) strain of P. aeruginosa to a high dose of colistin.

Susceptibility profiles and resistance genomics of Pseudomonas aeruginosa isolates from European ICUs participating in the ASPIRE-ICU trial.

Objectives: To determine the susceptibility profiles and the resistome of Pseudomonas aeruginosa isolates from European ICUs during a prospective cohort study (ASPIRE-ICU).

Methods: 723 isolates from respiratory samples or perianal swabs of 402 patients from 29 sites in 11 countries were studied. MICs of 12 antibiotics were determined by broth microdilution.

Evolutionary Processes Driving the Rise and Fall of ST239, a Dominant Hybrid Pathogen.

Selection plays a key role in the spread of antibiotic resistance, but the evolutionary drivers of clinically important resistant strains remain poorly understood. Here, we use genomic analyses and competition experiments to study Staphylococcus aureus ST239, a prominent MRSA strain that is thought to have been formed by large-scale recombination between ST8 and ST30. Genomic analyses allowed us to refine the hybrid model for the origin of ST239 and to date the origin of ST239 to 1920 to 1945, which predates the clinical introduction of methicillin in 1959.

Staphylococcal phages and pathogenicity islands drive plasmid evolution.

Conjugation has classically been considered the main mechanism driving plasmid transfer in nature. Yet bacteria frequently carry so-called non-transmissible plasmids, raising questions about how these plasmids spread. Interestingly, the size of many mobilisable and non-transmissible plasmids coincides with the average size of phages (~40 kb) or that of a family of pathogenicity islands, the phage-inducible chromosomal islands (PICIs, ~11 kb).

Evolutionary constraints on the acquisition of antimicrobial peptide resistance in bacterial pathogens.

Antimicrobial peptides (AMPs) offer a potential solution to the antibiotic resistance crisis. Recent studies have revealed important evolutionary constraints on the evolution and horizontal spread of AMP resistance in bacteria. Here, we summarize these advances and highlight their importance for therapeutic development of AMPs.

Integron activity accelerates the evolution of antibiotic resistance.

Mobile integrons are widespread genetic platforms that allow bacteria to modulate the expression of antibiotic resistance cassettes by shuffling their position from a common promoter. Antibiotic stress induces the expression of an integrase that excises and integrates cassettes, and this unique recombination and expression system is thought to allow bacteria to 'evolve on demand' in response to antibiotic pressure. To test this hypothesis, we inserted a custom three-cassette integron into and used experimental evolution to measure the impact of integrase activity on adaptation to gentamicin.

Beyond horizontal gene transfer: the role of plasmids in bacterial evolution.

Plasmids have a key role in bacterial ecology and evolution because they mobilize accessory genes by horizontal gene transfer. However, recent studies have revealed that the evolutionary impact of plasmids goes above and beyond their being mere gene delivery platforms. Plasmids are usually kept at multiple copies per cell, producing islands of polyploidy in the bacterial genome.

CRISPR-Cas systems restrict horizontal gene transfer in Pseudomonas aeruginosa.

CRISPR-Cas systems provide bacteria and archaea with an adaptive immune system that targets foreign DNA. However, the xenogenic nature of immunity provided by CRISPR-Cas raises the possibility that these systems may constrain horizontal gene transfer. Here we test this hypothesis in the opportunistic pathogen Pseudomonas aeruginosa, which has emerged as an important model system for understanding CRISPR-Cas function.

Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates.

The rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. Here, we test this hypothesis by challenging a diverse set of 222 isolates of Staphylococcus aureus with the antibiotic ciprofloxacin in a large-scale evolution experiment. We find that a single efflux pump, norA, causes widespread variation in evolvability across isolates.

Stochastic bacterial population dynamics restrict the establishment of antibiotic resistance from single cells.

A better understanding of how antibiotic exposure impacts the evolution of resistance in bacterial populations is crucial for designing more sustainable treatment strategies. The conventional approach to this question is to measure the range of concentrations over which resistant strain(s) are selectively favored over a sensitive strain. Here, we instead investigate how antibiotic concentration impacts the initial establishment of resistance from single cells, mimicking the clonal expansion of a resistant lineage following mutation or horizontal gene transfer.

Efficiently Simulating an Endograft Deployment: A Methodology for Detailed CFD Analyses.

Numerical models of endografts for the simulation of endovascular aneurysm repair are increasingly important in the improvement of device designs and patient outcomes. Nevertheless, current finite element analysis (FEA) models of complete endograft devices come at a high computational cost, requiring days of runtime, therefore restricting their applicability. In the current study, an efficient FEA model of the Anaconda™ endograft (Terumo Aortic, UK) was developed, able to yield results in just over 4 h, an order of magnitude less than similar models found in the literature.