Mechanisms of Daptomycin Non-susceptibility in Clinical Isolates of Staphylococcus aureus
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Issue Date
2016
Authors
Oliva, George Louis '16
Degree
MS in Pharmaceutical Sciences
Advisor
Malik, Meenakshi
Committee Members
Voigt, Jeffrey M.
Musteata, Marcel F
Musteata, Marcel F
Journal Title
Journal ISSN
Volume Title
Abstract
Methicillin resistant Staphylococcus aureus (MRSA) is responsible for a variety of nosocomial infections including skin and soft tissue infections, bacteremia, endocarditis, and toxic shock syndrome. Antibiotic resistance in MRSA strains has resulted in treatment failures posing a major clinical threat. The extensive use of daptomycin for treating MRSA infections has led to the emergence of daptomycin non-susceptible Staphylococcus aureus strains. Changes in the composition of cell membrane and cell wall leading to decreased daptomycin surface binding have been reported to be the cause of daptomycin resistance. Previous studies suggest that genes involved in regulation of transcription, cell wall biosynthesis, cell wall charge, autolysis and oxidative stress are principally responsible for induction of daptomycin resistance. The present study used three clinical isolates of daptomycin susceptible (DSSA) strains along with their daptomycin non-susceptible (DNSA) isogenic counterparts to study the phenotypic characteristics, gene expression profiles, and genetic mutations associated with daptomycin resistance. Our results unravel some of the complex molecular mechanisms of daptomycin resistance associated with increased cell membrane charge and cell wall thickness. The study serves as an important step forward in the development of phenotypic and genetic markers for rapid diagnosis of daptomycin non-susceptible strains of S. aureus. Additionally, the knowledge gained from these studies will be useful in determining alternative dosing and combination antibiotic regimens in clinical settings.
Citation
Oliva, GL. Mechanisms of daptomycin non-susceptibility in clinical isolates of Staphylococcus Aureus [thesis]. Ann Arbor (MI): Proquest LLC; 2016. 78 p.
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