Staphylococcus aureus JH9 VISA strain
   
   
 

The purpose of this sequencing project is to understand the genetic basis of a drug resistance mechanism as it emerges in the in vivo environment under the selective pressure of the antimicrobial agent vancomycin. The proposal involves sequencing a pair of isogenic methicillin resistant S. aureus (MRSA) strains that were recently recovered from a patient undergoing extensive chemotherapy with vancomycin (Sieradzki, K., T. Leski, L. Borio, J. Dick, and A. Tomasz.. 2003. Evolution of VISA strain in vivo: multiple genetic changes in a single lineage of MRSA under the impact of antibiotics administered for chemotherapy. J. Clin. Microbiol. 41: 1687-1693). The chronologically earliest isolate (JH1), recovered before the onset of vancomycin therapy, is susceptible to vancomycin and the “latest” isolate (JH9) – recovered shortly before the death of the patient has an increased vancomycin resistance. The range of change in antibiotic susceptibility and the altered physiological and biochemical properties of the strains indicate that strain JH9 represent the so-called VISA type vancomycin resistance which appeared in clinical specimen of MRSA in several countries during the last decade (Walsh, T.R., and R. A. Howe. 2002. The Prevalence and Mechanisms of Vancomycin Resistance in Staphylococcus aureus. Annu. Rev. Microbiol. 56:657-75). Several types of tests indicate that the earliest (JH1) and latest (JH9) isolates, and also the additional isolates recovered with intermediate levels of vancomycin resistance between JH1 and JH9 – are all “isogenic” bacteria by the most exacting molecular criteria (see project description). Therefore, the comparison of sequence differences between the first (“parental”, JH1) and the last (“mutant”, JH9) isolates should allow one to identify the genetic basis of vancomycin resistance. The project should enable us to reconstruct – for the first time – the evolutionary history of a bacterial pathogen in vivo, in a patient undergoing chemotherapy. At the end of therapy the bacterium emerges resistant to vancomycin, an antimicrobial agent most frequently used against one of the most important nosocomial pathogens.