Marion Helfand, M.D., Ph.D.
Assistant Professor of Medicine, Case Western Reserve University
Staff physician, Louis Stokes VAMC
Education
PhD-Chemistry University of California, Berkeley 1989
MD-Case Western Reserve University 1996
Special Training
Infectious Diseases, University Hospitals of Cleveland 2002
Patient Appointments 216-791-3800 x4608
Office 216-791-3800 x4672
Email marion.helfand@case.edu
Research Area
Structural biology of antimicrobial resistance
Research
The primary focus of my research is to understand how subtle
structural changes in proteins manifest themselves as drug resistance
in pathogenic organisms. Current research efforts are targeted
at understanding the structural basis of resistance to ß-lactamase
inhibitors brought about by point mutations in SHVß-lactamase
using a variety of molecular biological, computational and biophysical
methods.
In conjunction with the Carey and van den Akker labs (CWRU
Dept. of Biochemistry), we have developed a novel methodology
combining Raman microscopy and X-ray crystallography to trap
inhibited enzymes “in the act” of being inhibited.
Raman crystallography of a unique deacylation deficient SHV
ß-lactamase (E166A) with ß-lactamase inhibitors
reveals why tazobactam may be a superior clinical inhibitor.
Tazobactam forms twice as much stable inhibiting trans-enamine
intermediate as sulbactam or clavulanic acid Helfand, Totir
et al Biochemistry (2003)
Tazobactam inhibited E166A SHV crystals, flash frozen and diffracted
at the maximum of trans-enamine formation, reveal several unique
structural reasons for the enhanced production of a stable inhibition
intermediate by tazobactam—intramolecular H-bonding between
the trans-enamine NH and the sulfone S=O and interactions between
the triazole ring and water 49, Lys234 and Ser130 of the protein
(Padayatti, et al. 2003, submitted). Studies with inhibitor
resistant ß-lactamases are being undertaken.
Selected Publications
• Helfand, M. S., A. M. Hujer, F. D. Sonnichsen, and
R. A. Bonomo. 2002.
Unexpected Advanced Generation Cephalosporinase Activity of
the Met69Phe Mutant of SHV ß-Lactamase. Journal of Biological
Chemistry 277:47719.
• Helfand, M. S., and R. A. Bonomo. 2003.
ß-lactamases: a survey of protein diversity. Curr Drug
Targets Infect Disord. 3:9.
• Helfand, M. S., C. R. Bethel, A. M. Hujer, and R. A.
Bonomo.
Understanding Resistance to ß-lactams and ß-lactamase
inhibitors in the SHV ß -lactamase: lessons from the mutagenesis
of Ser130. Journal of Biological Chemistry. (Oct 8 E-pub ahead
of print).
• Helfand, M. S., M. A. Totir, A. M. Hujer, R. A. Bonomo,
and P. R. Carey. 2003.
Following the Reactions of Mechanism-Based Inhibitors with ß-Lactamase
by Raman Crystallography. Biochemistry 42:13386.
