Dean Rowe-Magnus

From

Dean Rowe-Magnus
Sunnybrook & Womens College Health Science Centre, Rm S1-26A
416-480-6100

Horizontal gene transfer has been a fundamental force in the rapid evolution of antibiotic resistance among diverse bacteria over the last 60 years. At the root of this phenomenon are integrons, genetic recombination systems that capture and express foreign DNA, called gene cassettes, which encode adaptive functions. The most notable gene cassettes identified within integrons are those conferring resistance to antibiotics. More than 70 different antibiotic resistance genes, covering most classes of antimicrobials presently in use, are structured as gene cassettes. The stockpiling of these cassettes in integrons has contributed substantially to the current dilemma in the treatment of infectious disease, as integrons containing up to 8 resistance cassettes have been found in multiple-resistant clinical isolates. The association of integrons with mobile DNA elements facilitates their transit across phylogenetic boundaries and augments the impact of integrons on bacterial evolution.

We recently showed that the impact of integrons on bacterial evolution has extended far beyond the 60 years of the antibiotic era. We discovered massive ancestral chromosomal versions, the super-integrons (SIs), in the genomes of diverse human, animal and plant pathogenic bacteria. The first was discovered in the Vibrio cholerae genome. Located on the smaller of the two circular V. cholerae chromosomes, this SI spanned 126 Kb and harbored 179 cassettes of mainly unassigned function, dwarfing any previously described antibiotic resistance integron. Although the vast majority of SI gene cassettes were of unknown function, some of the genes they harbored were related to the virulence and antibiotic resistance determinants characterized in clinical isolates. This suggested that the activity of integrons permitted bacteria to rapidly adapt to the unpredictable flux of environmental niches by scavenging foreign genes that may ultimately endow the bacterium with an adaptive advantage. If this is true, then the gene capture activity of SIs will have played an important role in the evolution of the bacteria in which they are found through the acquisition of functions that play specific roles in the adaptation of the bacteria to its particular niche.

Our lab is addressing this hypothesis by characterizing the SI of the pathogen Vibrio vulnificus. Vibrio vulnificus is a marine bacterium that can also colonize shellfish, eels and humans, 4 markedly different habitats. It is pathogenic to both humans and animals. The bacterium is highly invasive, causing primary septicimia and wound infections worldwide. The fatality rate of susceptible patients with primary septicimia can reach 75%, and death often occurs within hours of hospital admission. It alone is responsible for 95% of all seafood-related deaths in the United States and it carries the highest death rate of any food-borne disease agent. This bacterium harbors a SI. Our objective is to establish the extent to which the V. vulnificus SI has influenced the evolution of the bacterium by characterizing its SI through the sequencing and annotation of the roughly 140 Kb structure, the use of in vitro biochemical analysis, in vivo genetic manipulation, and DNA array and expression analysis. These studies will allow us to begin addressing questions about the role of the SI in the evolution of V. vulnificus as a potent human and successful environmental organism.

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