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Microbes run the world. It’s that simple. Although we cannot usually see them, microbes are essential for every part of human life—indeed all life on Earth. Every process in the biosphere is touched by the seemingly endless capacity of microbes to transform the world around them. The focus of our research is to explore this unseen biological diversity from a molecular perspective. We employ comparative genomics, experimental evolution and population genetics methods to learn about how microbes interact, how they evolve, and how they can be used to solve human health challenges. More recently we have refocused our lab effort in the area of drug discovery and development. However, we use our understanding of microbial ecology and evolution to identify drugs that are less “resistable” by the pathogens, that more specifically target the pathogens and leave the majority of the microbiome untouched, and that are far less toxic than most conventional antibiotics.
Rethinking the Composition of a rational antibiotic arsenal for the 21st century
The importance of the human microbiome in health may be the single most valuable development in our conception of the microbial world since Pasteur’s germ theory of the 1860s. Its implications for our understanding of health and pathogenesis are profound. Coupled with the revolution in diagnostics that we are now witnessing – a revolution that changes medicine from a science of symptoms to a science of causes – we cannot continue to develop antibiotics as we have for the past 80 years. Instead, we need to usher in a new conception of the role of antibiotics in treatment: away from single molecules that target broad phylogenetic spectra and towards targeted molecules that cripple the pathogen while leaving the rest of the microbiome largely intact. (Riley et al., 2013)
Bacteriocin-based Drug Development Platform
We are partnering with the Pheromonicin Biotech Ltd in Beijing to create a novel drug platform based upon bacteriocins. For more information see the PBL website.
The Evolution of Antibiotic Resistance
Pathogenic bacteria resistant to many or all antibiotics already exist. Coupled with the rapid decline in microbiological research at pharmaceutical companies, the rapid rate at which resistance has evolved and spread has demanded a novel approach to addressing this critical human health issue. Here we propose a new paradigm in antibiotic discovery and development, one that applies ecological and evolutionary theory to design antimicrobial drugs that are more difficult and/or more costly to resist. In essence, we propose to simply adopt the strategies invented and applied by bacteria for the past several billion years. Our research has revealed the manner in which bacteria create and deploy a powerful arsenal of biological weapons that maintain their efficacy for hundreds of millions of years.
The Role of Bacteriocins in Mediating Bacterial Competitive Interactions
Explaining the coexistence of competing species is a major challenge in community ecology. In bacterial systems, competition is often driven by the production of bacteriocins, which are narrow-spectrum proteinaceous toxins that serve to kill closely related species, providing the producer better access to limited resources. Bacteriocin producers have been shown to competitively exclude sensitive, nonproducing strains. However, the dynamics between bacteriocin producers, each lethal to its competitor, are largely unknown. In this study, we used in vitro, in vivo and in silico models to study competitive interactions between bacteriocin producers. Two Escherichia coli strains were generated, each carrying a DNA-degrading bacteriocin (colicins E2 and E7). Using reporter-gene assays, we showed that each DNase bacteriocin is not only lethal to its opponent but, at lower doses, can also induce the expression of its opponent’s toxin. In a well-mixed habitat, the E2 producer outcompeted its adversary; however, in structured environments (on plates or in mice colons), the two producers coexisted in a spatially ‘frozen’ pattern. Coexistence occurred when the producers were initiated with a clumped spatial distribution. This suggests that a ‘clump’ of each producer can block invasion of the other producer. Agent-based simulation of bacteriocin-mediated competition further showed that mutual exclusion in a structured environment is a relatively robust result. These models imply that colicin-mediated colicin induction enables producers to successfully compete and defend their niche against invaders. This suggests that localized interactions between producers of DNA-degrading toxins can lead to stable coexistence of heterogeneously distributed strains within the bacterial community and to the maintenance of diversity. Riley 2011
The Identification of Novel Antibiotics for use in Treating Lung Infections in Cystic Fibrosis
Pseudomonas aeruginosa (Pa) and Burkholderia cepacia complex (Bcc) lung infections are responsible for much of the mortality in cystic fibrosis (CF). However, little is known about the ecological interactions between these two, often co-infecting, species. This research addresses what is believed to be the first report of the intra- and interspecies bacteriocin-like inhibition potential of Pa and Bcc strains recovered from CF patients. Strains of both species were screened, and shown to possess bacteriocin-like inhibitory activity (97% of Pa strains and 68% of Bcc strains showed inhibitory activity), much of which acted across species boundaries. Further phenotypic and molecular-based assays revealed that the source of this inhibition differs for the two species. In Pa, much of the inhibitory activity is due to the well-known S and RF pyocins. In contrast, Bcc inhibition is due to unknown mechanisms, although RF-like toxins were implicated in some strains. These data suggest that bacteriocin-based inhibition may play a role in governing Pa and Bcc interactions in the CF lung and may, therefore, offer a novel approach to mediating these often fatal infections. Bakkal 2010
Catheter-Associated Urinary Tract Infections
We are currently investigating the use of bacteriocins to treat catheter-associated urinary tract infections (CAUTI), which are the most common nosocomial infection in the US with 1 million cases per year. To date we have shown that bacteriocins are as effective as traditional antibiotics at inhibiting the growth of uropathogenic E. coli. They are also able to kill their targets instantaneously and maintain a sterile environment over the course of 72 hours. We have also shown that the use of combinations of bacteriocins results in a reduction in the emergence of resistance to these antimicrobials. Bacteriocins have so much potential as a new therapeutic for CAUTI because there are bacteriocins that are able to target the most common species implicated in CAUTI. Riley 2012
The Bacterial Species Concept
The goal of this work is to evaluate the core genome hypothesis, which posits that there is a core set of shared genes that define a bacterial species. Although it is clear that mechanisms exist for abundant and widespread genetic transfer between microbial lineages, the observation of phenotypic clustering argues for genomic stability and cohesion. To evaluate the importance of genomic and evolutionary stability versus genomic flux, we employ population and comparative genomic methods. Such analyses suggest that, for at least E. coli and S. enterica, there is a core genome that is shared within, but not between, these two related species. If the core genome hypothesis holds for many bacterial lineages, then it may be possible to revise the existing Biological Species Concept originally proposed by Ernst Mayr such that is can be usefully applied to bacteria. Riley 2009