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      Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing.

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          Abstract

          The spread of multidrug-resistant Staphylococcus aureus (MRSA) strains in the clinical environment has begun to pose serious limits to treatment options. Yet virtually nothing is known about how resistance traits are acquired in vivo. Here, we apply the power of whole-genome sequencing to identify steps in the evolution of multidrug resistance in isogenic S. aureus isolates recovered periodically from the bloodstream of a patient undergoing chemotherapy with vancomycin and other antibiotics. After extensive therapy, the bacterium developed resistance, and treatment failed. Sequencing the first vancomycin susceptible isolate and the last vancomycin nonsusceptible isolate identified genome wide only 35 point mutations in 31 loci. These mutations appeared in a sequential order in isolates that were recovered at intermittent times during chemotherapy in parallel with increasing levels of resistance. The vancomycin nonsusceptible isolates also showed a 100-fold decrease in susceptibility to daptomycin, although this antibiotic was not used in the therapy. One of the mutated loci associated with decreasing vancomycin susceptibility (the vraR operon) was found to also carry mutations in six additional vancomycin nonsusceptible S. aureus isolates belonging to different genetic backgrounds and recovered from different geographic sites. As costs drop, whole-genome sequencing will become a useful tool in elucidating complex pathways of in vivo evolution in bacterial pathogens.

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          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proceedings of the National Academy of Sciences of the United States of America
          Proceedings of the National Academy of Sciences
          0027-8424
          0027-8424
          May 29 2007
          : 104
          : 22
          Affiliations
          [1 ] Physics Department, Cornell University, Ithaca, NY 14850, USA.
          Article
          0609839104
          10.1073/pnas.0609839104
          1890515
          17517606
          daff1021-6b28-4e1b-94da-657da5ca0d3e
          History

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