Researchers at the University of British Columbia have identified a small molecule that prevents bacteria from forming into biofilms, a frequent cause of infections. The anti-biofilm peptide works on a range of bacteria including many that cannot be treated by antibiotics.
“Currently there is a severe problem with antibiotic-resistant organisms,” says Bob Hancock, a professor in UBC’s Dept. of Microbiology and Immunology and lead author of the study published today in PLOS Pathogens. “Our entire arsenal of antibiotics is gradually losing effectiveness.”
Many bacteria that grow on skin, lung, heart and other human tissue surfaces form biofilms, highly structured communities of bacteria that are responsible for two-thirds of all human infections. There are currently no approved treatments for biofilm infections and bacteria in biofilms are considerably more resistant to standard antibiotics.
Hancock and his colleagues found that the peptide known as 1018–consisting of just 12 amino acids, the building blocks of protein–destroyed biofilms and prevented them from forming.
Bacteria are generally separated into two classes, Gram-positives and Gram-negatives, and the differences in their cell wall structures make them susceptible to different antibiotics. 1018 worked on both classes of bacteria as well as several major antibiotic-resistant pathogens, including E. coli, Pseudomonas aeruginosa and MRSA.
“Antibiotics are the most successful medicine on the planet. The lack of effective antibiotics would lead to profound difficulties with major surgeries, some chemotherapy treatments, transplants, and even minor injuries,” says Hancock. “Our strategy represents a significant advance in the search for new agents that specifically target bacterial biofilms.”
The opportunistic pathogen Pseudomonas aeruginosa uses a cell-cell communication system termed “quorum sensing” to control production of public goods, extracellular products that can be used by any community member. Not all individuals respond to quorum-sensing signals and synthesize public goods. Such social cheaters enjoy the benefits of the products secreted by cooperators. There are some P. aeruginosa cellular enzymes controlled by quorum sensing, and we show that quorum sensing–controlled expression of such private goods can put a metabolic constraint on social cheating and prevent a tragedy of the commons. Metabolic constraint of social cheating provides an explanation for private-goods regulation by a cooperative system and has general implications for population biology, infection control, and stabilization of quorum-sensing circuits in synthetic biology.
Metabolic crossfeeding is an important process that can broadly shape microbial communities. However, little is known about specific crossfeeding principles that drive the formation and maintenance of individuals within a mixed population. Here, we devised a series of synthetic syntrophic communities to probe the complex interactions underlying metabolic exchange of amino acids. We experimentally analyzed multimember, multidimensional communities of Escherichia coli of increasing sophistication to assess the outcomes of synergistic crossfeeding. We find that biosynthetically costly amino acids including methionine, lysine, isoleucine, arginine, and aromatics, tend to promote stronger cooperative interactions than amino acids that are cheaper to produce. Furthermore, cells that share common intermediates along branching pathways yielded more synergistic growth, but exhibited many instances of both positive and negative epistasis when these interactions scaled to higher dimensions. In more complex communities, we find certain members exhibiting keystone species-like behavior that drastically impact the community dynamics. Based on comparative genomic analysis of >6,000 sequenced bacteria from diverse environments, we present evidence suggesting that amino acid biosynthesis has been broadly optimized to reduce individual metabolic burden in favor of enhanced crossfeeding to support synergistic growth across the biosphere. These results improve our basic understanding of microbial syntrophy while also highlighting the utility and limitations of current modeling approaches to describe the dynamic complexities underlying microbial ecosystems. This work sets the foundation for future endeavors to resolve key questions in microbial ecology and evolution, and presents a platform to develop better and more robust engineered synthetic communities for industrial biotechnology.
Experts weigh in on the biggest obstacles in synthetic biology — from names to knowledge gaps — and what it will take to overcome them.
The engineering slant of synthetic biology has brought impressive accomplishments. These include whole-cell biosensors; cells that synthesize antimalaria drugs; and bacterial viruses designed to disperse dangerous, tenacious biofilms.
To design these, engineers are trained to model systems as black boxes, abstractly linking inputs and outputs. They can often control a system with only a limited understanding of it. But synthetic-biology projects are frequently thwarted when engineering runs up against the complexity of biology.
Synthetic biology would benefit greatly from deeper insights into the mechanisms of biological systems. Such approaches have already yielded insights into how organized processes in cells work because of, rather than in spite of, noisy gene expression. Synthetic biology is also informing biology, helping to reveal how a gene product can amplify or inhibit its own expression and so allow cells to flip between stable states. Much more remains to be explored and discovered.
The biggest challenge for synthetic biology is how to extend beyond projects that focus on single products, organisms and processes. Right now, most applications engineer bacteria that start a synthesis with glucose and turn out biofuels or fine chemicals, such as vanillin or artemesinin. A broader scope could help to build a 'greener' economy, in which more organisms make a greater range of chemicals.
The chemical industry is a marvel of efficiency, taking raw materials such as oil and converting them into a wide range of products, including plastics and pharmaceuticals. This is possible in part because feedstocks can be interconverted through various large-scale reactions for which catalysts and processes have been optimized over several decades.
Synthetic biology could unlock the large-scale use of carbon sources from lignocellulose to coal. Synthetic 'bioalchemy' would reformat the basic elements of life to take advantage of abundant supplies of formerly rare intermediates such as the nylon precursor adipate, which is used to synthesize antibiotics. Metabolic engineering is already capable of syntheses that use glucose or other standard carbon sources as precursors, but the co-culture of synthetically modified organisms would make these processes more efficient. The ability to engineer photosynthetic organisms might even allow light to be used as the ultimate energy source and carbon dioxide as the ultimate carbon source.
Vibrio cholerae, the scourge of nations lacking clean water. Pseudomonas aeruginosa, the microbe that plagues people with cystic fibrosis.Acinetobacter species, opportunistic organisms that can infect vulnerable people. Escherichia coli, a culprit in food-borne illnesses.
When these bacteria invade their human hosts, they can cause misery and death. But these pathogens also do battle with each other—if provoked. New research sheds light on the tiny war machines that bacteria wield in surprisingly precise and selective counterattacks against their bacterial foes. Real-time fluorescent microscopy catches what HMS scientists call “bacterial tit-for-tat.”
John Mekalanos, HMS Adele Lehman Professor of Microbiology and Molecular Genetics and head of the Department of Microbiology and Immunobiology, last year noted “T6SS dueling” among bacteria of the same species. The name describes the interactions between two sister cells’ type 6 secretion systems. These dynamic nanomachines can deliver a toxic protein by piercing the threatening cell. A previous postdoctoral fellow in the Mekalanos lab, Joseph Mougous (now at the University of Washington, Seattle) discovered that immunity proteins likely protect these sister cells from such attacks. But the fact that the sisters fight back was appreciated only when Marek Basler, a research fellow in Microbiology and Immunobiology, and Mekalanos watched these pitched battles under the microscope.
Recent examples of new genetic circuits that enable cells to acquire biosynthetic capabilities, such as specific pathogen killing, present an attractive therapeutic application of synthetic biology. A team of researchers in Singapore has developed a technique for bioengineering a bacterium to seek out and kill targeted pathogens.
They demonstrate a novel genetic circuit that reprograms Escherichia coli to specifically recognize, migrate toward, and eradicate both dispersed and biofilm-encased pathogenic Pseudomonas aeruginosa cells. The reprogrammed E. coli degraded the mature biofilm matrix and killed the latent cells encapsulated within by expressing and secreting the antimicrobial peptide microcin S and the nuclease DNaseI upon the detection of quorum sensing molecules naturally secreted by P. aeruginosa. Furthermore, the reprogrammed E. coli exhibited directed motility toward the pathogen through regulated expression of CheZ in response to the quorum sensing molecules.
By integrating the pathogen-directed motility with the dual antimicrobial activity in E. coli, we achieved signifincantly improved killing activity against planktonic and mature biofilm cells due to target localization, thus creating an active pathogen seeking killer E. coli.
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