Staphylococcus aureus is a leading cause of community and nosocomially-acquired infectious and toxin-mediated syndromes, some life threatening, that affect patients of all ages. The glycopeptides (GP) have been the most reliable alternatives for the therapy of S. aureus isolates that are resistant to methicillin, cross resistant to all beta-lactams, and often resistant to a wide spectrum of unrelated antimicrobials. However, the effectiveness of GPs has been eroded by the increasing recognition of resistant isolates. Our ongoing studies are aimed at identifying GP resistance mechanisms. Despite the description of numerous phenotypic and biochemical characteristics among resistant isolates, the mechanism(s) of GP resistance in S. aureus has remained incompletely defined. Available data suggest that acquisition of the resistance phenotype involves cell wall reorganization; pleiotropic changes have been documented such as altered peptidoglycan structure, coagulase activity, binding of vancomycin, autolytic activity and lysostaphin susceptibility. However, it seems unlikely that a single mechanism or sequence of mechanisms will account for resistance in all clinical glycopeptide-resistant isolates studied to date since no phenotypic or biochemical change has been uniformly found. We believe that the resistant phenotype involves multiple genetic changes. We plan to investigate the mechanism(s) of resistance with a multi-pronged approach. First, with the complete genomic sequence of four S. aureus isolates at hand, we will employ microarray analysis to compare expression patterns of relevant cell wall metabolic and 2-component signal transduction genes between GP-susceptible and resistant isolates. The availability of isogenic susceptible and resistant clinical isolate pairs will provide invaluable tools for this analysis. Appropriate up and down regulated genes will be targeted for further investigation including sequence comparison, Northern blot analysis, allelic inactivation and overexpression in relevant genetic backgrounds. These studies should lead to an understanding of the mechanisms by which S. aureus resist the bactericidal effect of GPs and hopefully can identify new ideas regarding therapy of infections caused by resistant isolates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040481-05
Application #
6726143
Study Section
Special Emphasis Panel (ZRG1-BM-1 (02))
Program Officer
Peters, Kent
Project Start
1998-11-15
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
5
Fiscal Year
2004
Total Cost
$381,250
Indirect Cost
Name
University of Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005421136
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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