Cystic fibrosis (CF) is a genetic disease that affects the lungs and other organs. People with CF have a defect in a protein called CFTR, which regulates the movement of salt and water across cell membranes. This causes the mucus in the lungs to become thick and sticky, making it hard to clear and creating an ideal environment for bacterial infections1.
One of the most common and persistent pathogens in CF patients is Staphylococcus aureus, a bacterium that can cause pneumonia, sepsis, and other serious complications. S. aureus can form biofilms, which are communities of bacteria embedded in a matrix of extracellular substances. Biofilms protect bacteria from antibiotics, immune cells, and environmental stresses, and make them more difficult to eradicate2.
To better understand and treat biofilm infections in CF patients, scientists from the University of Nottingham have engineered a living material that resembles human phlegm, or sputum, which is the mixture of mucus and saliva that is coughed up by CF patients. The material can grow 3D polymicrobial biofilms, which are biofilms composed of multiple species of bacteria, in a controlled manner, mimicking those found in the CF lung3.
The researchers used peptides, which are short chains of amino acids, to create a scaffold that can support the growth of biofilms. They combined the peptides with an artificial sputum medium (ASM), which is a culture medium that simulates the chemical and physical properties of CF sputum. They then infected the material with different strains of S. aureus isolated from CF patients, and observed how they formed biofilms over time3.
The engineered material was able to reproduce the diversity and complexity of natural biofilms from CF sputum, including the presence of multiple microbial communities and key nutritional and chemical factors that promote bacterial growth. The material also exhibited physical properties similar to those of biofilms from CF sputum, such as viscosity, elasticity, and resistance to shear stress3.
The researchers used the material to build an infected in vitro lung epithelial model, which is a laboratory model that mimics the cells lining the airways of the lung. They used this model to study the impact of antibiotics on biofilm formation and eradication. They tested five antibiotics: ceftaroline, ceftobiprole, linezolid, trimethoprim, and rifampicin, and measured their minimum biofilm inhibitory concentrations (bMIC), which are the lowest concentrations of antibiotics that can prevent or reduce biofilm formation3.
The results showed that the bMICs varied depending on the strain of S. aureus and the antibiotic used. The broad-spectrum cephalosporins, ceftaroline and ceftobiprole, had the lowest bMICs on a majority of strains, followed by linezolid, a synthetic antibiotic that targets protein synthesis. Trimethoprim and rifampicin, which are commonly used to treat S. aureus infections, had the highest bMICs and were less effective against biofilms3.
The researchers also focused on four chronically colonized patients, who had multiple isolates of S. aureus collected over time. They found that the bMICs of ceftaroline, ceftobiprole, and linezolid remained below the resistance thresholds over time, suggesting that these antibiotics could be useful for long-term treatment of biofilm infections in CF patients3.
To further investigate the dynamics of biofilm formation and inhibition, the researchers used a microfluidic system called BioFlux™ 200, which allows the continuous flow of fluids and the observation of biofilms under a microscope. They studied two strains of S. aureus isolated from one of the chronically colonized patients, three years apart. They exposed the biofilms to bMICs of ceftaroline, ceftobiprole, and linezolid, and monitored their growth and morphology for 36 hours3.
The results showed that all three antibiotics were able to inhibit biofilm formation for up to 36 hours, but ceftaroline and ceftobiprole had a significantly greater effect than linezolid. Ceftaroline and ceftobiprole reduced the biomass and thickness of the biofilms, and prevented the formation of mushroom-like structures, which are characteristic of mature biofilms. Linezolid, on the other hand, had a weaker effect on the biofilm structure, and allowed some bacterial cells to escape and form new biofilms3.
The researchers concluded that the engineered material they developed is a valuable tool for studying biofilm infections in CF patients, and for evaluating novel antimicrobial interventions. They also suggested that the combination of broad-spectrum cephalosporins and linezolid could be a promising strategy for treating biofilm infections in CF patients, as they have different modes of action and synergistic effects3.
The study, published in the journal Matter, was led by Dr. Yuanhao Wu and is a collaboration between Professor Alvaro Mata in the School of Pharmacy and Department of Chemical Engineering and Professor Miguel Cámara from the National Biofilms Innovation Center in the School of Life Sciences at the University of Nottingham3.
1: Cystic fibrosis - Symptoms and causes - Mayo Clinic 2: Biofilm Formation in Methicillin-Resistant - Frontiers 3: News - Scientists take a step forward in understanding how to tackle …
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