|
BIOGRAPHY:
Dr. Strynadka received her Ph.D. in structural biology from the University of Alberta in 1990, where she subsequently conducted postdoctoral research in the Departments of Biochemistry and Microbiology until being given the position of Research Fellow in 1995. In 1997 she achieved her current position of Assistant Professor of the Department of Biochemistry of the University of British Columbia in Vancouver, Canada. In 1997 she received the honor of being named a Medical Research Council of Canada Scholar. In 1998 she received the CFI New Opportunitues Award, and in 1999 was named a Burroughs Wellcome New Investigator in the Pharmacological Sciences. Her HHMI project involves structural characterization of bacterial membrane components with the goal of discovering new antibiotic targets.
RESEARCH ABSTRACT SUMMARY:
Taming the Superbugs: Structural and Inhibitory Analysis of the Key Determinant of Broad-Spectrum Beta-Lactam Resistance in
Methicillin-Resistant Strains of Staphylococcus aureus
The multiple antibiotic resistance of methicillinresistant strains
of Staphylococcus aureus (MRSA) has become a major clinical
problem worldwide in terms of both fatalities and containment costs.
The key determinant of broad-spectrum beta-lactam resistance in MRSA
superbug strains is the membrane-spanning penicillin-binding protein 2a
(PBP2a), a transpeptidase that is required to produce peptide
cross-links that give the bacterial cell wall its necessary strength
and rigidity. Due to its low affinity for beta-lactams, PBP2a provides
crosslinking transpeptidase activity at beta-lactam concentrations that
inhibit the other beta-lactam–sensitive cell-wall transpeptidases
normally produced by S. aureus and other pathogenic bacteria. The
crystal structure of PBP2a from MRSA strain 27r has been determined to
1.8 Å resolution. Structures of the acyl-enzyme complexes of PBP2a with
nitrocefin, penicillin G, and methicillin have also been determined to
high resolution and show for the first time beta-lactam binding by a
resistant transpeptidase. An analysis of the PBP2a active site reveals
the structural basis of its broad-spectrum resistance to the
approximately 50 clinically utilized beta-lactam antibiotics and
identifies features in beta-lactams important for high affinity
binding. This information has been used in structure-based inhibitor
design strategies aiming to combat this resistance in the MRSA
superbug.
Photo: Kent Kallberg, Kallberg Studios
|
