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Helen I. Zgurskaya

Helen I. Zgurskaya

Helen I. Zgurskaya

George Lynn Cross Research Professor

Research Areas: Biochemistry 
Office: SLSRC 3610

B.S., 1989, Dnepropetrovsk State University, Ukraine 
Ph.D., 1992, Russian Academy of Sciences, Russia
Postdoc, 1995-1996, Stanford University School of Medicine, Stanford, California
Postdoc, 1996-1999, University of California, Berkeley

Research Keywords:
cell membrane biochemistry, antibiotic resistance, drug permeation, multidrug efflux, membrane transporters

Research in Zgurskaya’s lab is focused on the permeability barriers of bacterial pathogens with the emphasis on quantitative and mechanistic characterization of membrane transporters, antibiotic permeation and active drug efflux. The lab develops experimental cell-based and biochemical assays to study permeation of compounds into bacteria and interactions between components of multidrug efflux pumps and their substrates and inhibitors. The lab is a member of the Center for Antibiotic Discovery and Resistance (CADR), an international team composed of 13 research groups spread across six academic campuses, Oak Ridge and Los Alamos National Laboratories. We conduct interdisciplinary collaborative research in three major areas:

1. Multidrug efflux and its inhibition.
Multidrug efflux is one of the major mechanisms of antibiotic resistance in bacteria. We have successfully purified, reconstituted into proteoliposomes and characterized multidrug transporters belonging to different protein families and organisms. By combining in vivo studies with comparative biochemistry, we have reconstructed the sequence of events leading to assembly of functional drug efflux complexes and the mechanism of activation of efflux pumps. With the team at CADR, we next developed a joint experimental and computational approach to discover efflux pump inhibitors that target the assembly of efflux pump complexes and discovered new classes of efflux inhibitors. We continue molecular and functional analyses of multidrug efflux to understand its role and mechanism in bacterial multidrug resistance phenomenon and to facilitate development of efflux pump inhibitors for clinical applications

Gram-negative cells with their envelope structure

2. Synergistic interactions between multidrug transporters and other mechanisms of resistance.
Efflux pumps are the most effective when function in cooperation with other mechanisms of antibiotic resistance. Current efforts in the lab are focused on analyses of functional interplay between active efflux and the low permeability barrier of the outer membrane. We developed a technology that allows separation of contribution of active efflux and passive uptake to the antibiotic efficacy. We are applying this technology to the discovery and optimization of clinical and experimental antibiotics for activities against multidrug resistant Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa.

3. Efflux and export transporters of Gram-positive bacteria and mycobacteria.
We initiated biochemical analyses of putative drug efflux pumps in Gram-positive bacteria. We analyzed the composition, assembly and function of the multi-component transporter YknWXYZ from a Gram-positive bacterium Bacillus subtilis involved in protection of this bacterium from SDP toxin. With a team of collaborators, we investigate the role of RND transporters in the biogenesis of the low-permeability barrier of the outer membrane of coryne- and myco-bacteria. We have established a new recombinant system for expression and biochemical analyses of RND transporters from these bacteria. Current efforts are focused on the mechanism of MmpL3 protein from Mycobacterium tuberculosis, the major target of anti-tuberculosis drug discovery efforts.


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Awards and Honors

George Lynn Cross Research Professor, 2019, University of Oklahoma