Staphylococcal species are a leading cause of nosocomial infections and a variety of infections and toxin mediated syndromes that affect patients of all ages. The glycopeptides (GP) vancomycin (Vm) and teicoplanin (Tco) are the most reliable alternatives for treatment of methicillin-resistant staphylococci, which are resistant to beta-lactams and a wide spectrum of antibiotics. Therefore, the emergence of clinical staphylococcal isolates with decreased susceptibility, heteroresistance, and true resistance to Gps has been alarming. The investigators' studies are aimed at identifying Vm and Tco resistance mechanisms in staphylococci. Resistance is likely to be complex and multifactorial and, thus, require a multifaceted investigative approach. In this regard, they propose to characterize a transposon (Tn) mutant of a Vm-resistant laboratory derived Staphylococcus aureus isolate and to perform Tn mutagenesis on other clinical Vm- and Tco-resistant S. aureus isolates and on a coagulase negative Vm-resistant S. haemolyticus isolate. They also plan to screen plasmid libraries prepared from selected glycopeptide- resistant clinical and laboratory isolate(s) for inserts capable of conferring Vm-resistance in Vm-susceptible isolates to determine the role of the plasmid insert in mediating resistance. They also propose to identify glycopeptide resistance determinants by global, random comparisons of genomic DNA and mRNA from resistant and susceptible isolates by restriction landmark genomic scanning and mRNA differential display aimed at comparing GP-resistant and -susceptible S. aureus isolates. The decision to undertake these will be based in part on what was learned with Tn mutagenesis and screening of the plasmid libraries. They will also determine whether there is a role for PBP2, found in increased abundance in many clinical and laboratory derived Vm-resistant isolates, by inactivating the pbpB gene and evaluating its effect on resistance and heteroresistance in staphylococci and employ an avian model of S. aureus bacteremia to begin to clarify some important issues regarding GP-resistance in S. aureus. These studies should lead to an understanding of the mechanisms by which staphylococci resist Gps and may provide novel protein targets against which antimicrobial agents could be designed to treat staphylococcal infections caused by GP resistant isolates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040481-02
Application #
6087501
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1998-11-15
Project End
2001-10-31
Budget Start
1999-11-01
Budget End
2000-10-31
Support Year
2
Fiscal Year
2000
Total Cost
$511,036
Indirect Cost
Name
University of Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Jones, Marcus B; Montgomery, Christopher P; Boyle-Vavra, Susan et al. (2014) Genomic and transcriptomic differences in community acquired methicillin resistant Staphylococcus aureus USA300 and USA400 strains. BMC Genomics 15:1145
Montgomery, Christopher P; Daniels, Melvin; Zhao, Fan et al. (2014) Protective immunity against recurrent Staphylococcus aureus skin infection requires antibody and interleukin-17A. Infect Immun 82:2125-34
Montgomery, Christopher P; Daniels, Melvin D; Zhao, Fan et al. (2013) Local inflammation exacerbates the severity of Staphylococcus aureus skin infection. PLoS One 8:e69508
Montgomery, Christopher P; Boyle-Vavra, Susan; Roux, Agnès et al. (2012) CodY deletion enhances in vivo virulence of community-associated methicillin-resistant Staphylococcus aureus clone USA300. Infect Immun 80:2382-9
Daum, Robert S; Spellberg, Brad (2012) Progress toward a Staphylococcus aureus vaccine. Clin Infect Dis 54:560-7
Montgomery, Christopher P; Boyle-Vavra, Susan; Daum, Robert S (2010) Importance of the global regulators Agr and SaeRS in the pathogenesis of CA-MRSA USA300 infection. PLoS One 5:e15177
Yang, Soo-Jin; Xiong, Yan Q; Boyle-Vavra, Susan et al. (2010) Daptomycin-oxacillin combinations in treatment of experimental endocarditis caused by daptomycin-nonsusceptible strains of methicillin-resistant Staphylococcus aureus with evolving oxacillin susceptibility (the ""seesaw effect""). Antimicrob Agents Chemother 54:3161-9
Montgomery, Christopher P; Daum, Robert S (2009) Transcription of inflammatory genes in the lung after infection with community-associated methicillin-resistant Staphylococcus aureus: a role for panton-valentine leukocidin? Infect Immun 77:2159-67
Daum, Robert S (2009) Epidemic community-associated methicillin-resistant Staphylococcus aureus infections--increasingly, everyone's problem. J AAPOS 13:225-6
Montgomery, Christopher P; Boyle-Vavra, Susan; Daum, Robert S (2009) The arginine catabolic mobile element is not associated with enhanced virulence in experimental invasive disease caused by the community-associated methicillin-resistant Staphylococcus aureus USA300 genetic background. Infect Immun 77:2650-6

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