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.