January 25, 2010

The Evolution And Spread Of Drug-Resistant Bacteria

An international team of researchers has used high resolution genome sequencing to track a particularly virulent strain of MRSA as it traveled between South America, Europe and Southeast Asia. The findings shed light on how these deadly bacteria are able to spread from patient to patient in a single hospital and, on a larger scale of geography and time, between countries and entire continents.

The researchers included scientists from Rockefeller University, the Wellcome Trust Sanger Institute and the University of Bath in the United Kingdom, Instituto de Tecnologia Química e Biol³gica (ITQB) in Portugal and a hospital in Thailand.

"MRSA is responsible for over 18,000 fatalities in the United States each year according to CDC estimates, a number virtually identical to the current fatality rate of AIDS in the USA," says Alexander Tomasz, who is Dr. Plutarch Papamarkou Professor and head of the Laboratory of Microbiology and Infectious Disease at Rockefeller.

Earlier studies by Rockefeller and ITQB scientists demonstrated that the most successful MRSA strains belong to a limited number of families, or clones, that are responsible for the overwhelming majority "” more than 80 percent "” of all MRSA disease in hospitals worldwide.

In the new research, the scientists focused on one of the most successful MRSA clones, called the Brazilian MRSA, which was first identified at Rockefeller in 1995 and which has the DNA sequence type assignment ST239 (SCCmec III). Isolates of Brazilian MRSA are resistant to virtually all currently available antibacterial agents except vancomycin.

Colleagues at ITQB in Portugal and Susana Gardete, a postdoctoral fellow in the Laboratory of Microbiology and Infectious Disease at Rockefeller, prepared DNA from more than 40 of the Brazilian MRSA isolates recovered between 1982 and 2003 from a variety of sources in Europe, South America and Asia. These preparations were analyzed by colleagues at the Sanger Institute using a new, very high throughput DNA sequencing technology.

The findings reported in Science provide an unparalleled view of the evolutionary history and age of the Brazilian MRSA clone. It was possible to show that the most likely birthplace of Brazilian MRSA was actually Europe, from where it spread to South America and Asia. From there, it continued to evolve and was reintroduced to Europe at a later date.

Applying the same technology to 20 Brazilian MRSA samples recovered from individual patients in a single Thai hospital within the short timeframe of a few weeks, the scientists were able to trace with precision the patient-to-patient spread of the MRSA bacterium.

"The remarkable insights that this study provides into the stages of evolution of a major human pathogen illustrates the power of collaboration between evolutionary biologists, experts in DNA sequencing and bioinformatics and epidemiologists who can provide carefully selected and characterized strain collections for each study," says Tomasz.

For more than 20 years, Tomasz and Hermínia de Lencastre, a senior research associate in his laboratory, have collected isolates of MRSA patients all over the world. These carefully characterized samples are stored in freezers at ITQB and Rockefeller as part of the CEM/NET Initiative, an ongoing international project in molecular epidemiology first organized by de Lencastre and Tomasz in 1995.

"The application of full genome sequencing described in the Science report provides us with a view of how MRSA evolves on two different scales of time and geography," says de Lencastre. "It not only documents evolution on the timescales of decades and over the geography of entire continents, but also on the shorter timescale of a few weeks within the confines of a single hospital in Thailand."

"It would be interesting to add to these two stories a third one in which we applied full DNA sequencing on an even shorter scale of time and space," says Tomasz. "In a recent study published in PNAS in 2007 we were able to track the in vivo evolution of multidrug resistance in a single MRSA lineage recovered from a patient undergoing a three-month course of chemotherapy."

Reference: Science 327: 469"“474 (January 21, 2010). Evolution of MRSA During Hospital Transmission and Intercontinental Spread. Simon R. Harris, Edward J. Feil, Matthew T. G. Holden, Michael A. Quail, Emma K. Nickerson, Narisara Chantratita, Susana Gardete, Ana Tavares, Nick Day, Jodi A. Lindsay, Jonathan D. Edgeworth, Hermínia de Lencastre, Julian Parkhill, Sharon J. Peacock and Stephen D. Bentley


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