MRSA and VISA strains continue to present serious challenge to the therapy of staphylococcal disease. Highly virulent and epidemic lineages have emerged among community acquired MRSA and treatment failure during vancomycin therapy continues to be reported in the clinical literature. As to the scientific challenges presented by drug resistant S. aureus: while several critical genetic determinants of the resistance mechanisms have been identified, the path leading from the resistant genes to the antibiotic resistant phenotype has remained an enigma in both MRSA and VISA strains. All clinical isolates of MRSA carry the same mecA gene encoding for the low antibiotic affinity protein PBP2a. Nevertheless, individual MRSA strains exhibit a vast range of oxacillin MIC values which can spread from a few micrograms up to the milligram range. Furthermore, the majority of MRSA isolates show a peculiar - heterogeneous - phenotype: such strains produce cultures in which the great majority of cells (99-99.9%) exhibit very low MIC values but the same cultures also contain one or more sub-populations of highly resistant bacteria which are present with low and unique frequencies. Besides presenting an intriguing scientific puzzle the phenomenon of hetero resistance may have important clinical implications as well, since selection of the highly resistant subpopulations in vivo may jeopardize the success of therapy. The mechanism by which these complex MRSA phenotypes are generated from the same mecA determinant is unknown. Similarly, genetic determinants associated with the acquisition of VISA type vancomycin resistance has been determined recently by full genome sequencing but the mechanism by which the increased vancomycin MIC value and the large number of phenotypic alterations are generated from the 33 specific mutations identified in the sequenced VISA strain JH9 [2] - remains to be determined. Thus, the common question posed for both the MRSA and VISA mechanisms in the new research program is this: how does one go from a resistance gene to the resistant phenotype? The studies in the new research program are organized into four major foci of activity. Project A. Genetic determinants of high level antibiotic resistance in heteroresistant MRSA clones. Project B. Genetic and environmental factors defining the antibiotic resistant phenotype in MRSA. Project C. Pathways of cell wall synthesis and antibiotic resistance level in MRSA. Project D. Genetic pathways to decreased vancomycin susceptibility.

Public Health Relevance

Multidrug resistant MRSA strains continue to spread both in hospitals and in the community and infections by these "superbugs" were estimated to cause close to 19,000 deaths and billions of dollars in health care costs per year in the USA. Clinical treatment failures with vancomycin - often called the "last resort" antibiotic - have also been described. We plan to use methods of modern science such as whole genome DNA sequencing to understand the mechanisms these dangerous pathogens have invented and to help develop new interventions that could reestablish control over multidrug resistant bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045738-13
Application #
8260491
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Huntley, Clayton C
Project Start
2000-03-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
13
Fiscal Year
2012
Total Cost
$569,437
Indirect Cost
$232,492
Name
Rockefeller University
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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Kim, Choonkeun; Mwangi, Michael; Chung, Marilyn et al. (2014) Correction: The Mechanism of Heterogeneous Beta-Lactam Resistance in MRSA: Key Role of the Stringent Stress Response. PLoS One 9:
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Hower, S; Wolf, K; Fields, K A (2009) Evidence that CT694 is a novel Chlamydia trachomatis T3S substrate capable of functioning during invasion or early cycle development. Mol Microbiol 72:1423-37
Gardete, S; Aires-De-Sousa, M; Faustino, A et al. (2008) Identification of the first vancomycin intermediate-resistant Staphylococcus aureus (VISA) isolate from a hospital in Portugal. Microb Drug Resist 14:1-6
Chung, Marilyn; Antignac, Aude; Kim, Choonkeun et al. (2008) Comparative study of the susceptibilities of major epidemic clones of methicillin-resistant Staphylococcus aureus to oxacillin and to the new broad-spectrum cephalosporin ceftobiprole. Antimicrob Agents Chemother 52:2709-17

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