Georgiana Purdy, Ph.D., is associate professor of molecular microbiology and immunology, OHSU School of Medicine.

October 2, 2015

What’s been the most interesting development in your area in the last two years?

Work in the Purdy Lab focuses on defining the pathogenesis and basic biology of Mycobacterium tuberculosis (Mtb) using a combination of bacterial genetics and biochemistry. Recent work from our group and others demonstrated that the mycobacterial membrane protein large (MmpL) proteins are essential and virulence-associated cell wall lipid transporters. In particular, we are interested in MmpL3 and Mmpl11 that are conserved across pathogenic and nonpathogenic mycobacteria. MmpL3 and MmpL11 transport mycolic acid-containing lipids. MmpL3 transports trehalose monomycolate (TMM) and is required for mycobacterial replication and viability. We demonstrated that MmpL11 transports monomeromycolyl diacylglycerol, a specialized triacylglycerol (TAG) molecule and mycolate ester wax. TAGs and wax esters are “storage lipids” associated with Mtb infection. Our working model is that MmpL3 and MmpL11 are conserved across mycobacteria because they are required for the two phases of mycobacterial existence. MmpL3 is essential for active replication because exported TMM is required for cell wall generation. MmpL11 is important for persistence because it is required for transport of “storage lipids.” In Mtb mutants that lack mmpL11, the bacterium is less able to survive long-term in mice and does not survive or recover from incubation in our in vitro models of latency.

Because MmpL proteins are important for cell wall remodeling, we are also exploring the regulation of MmpL protein expression in different environmental conditions. We have defined the structure and function of several Mtb transcriptional regulators that control expression of essential and virulence-associated MmpL proteins in collaboration with Dr. Edward Yu, Professor, Iowa State University. Our data indicate that fatty acids directly modulate activity of these unique transcription factors. Based on these data, we think that Mtb can directly assess and respond to fatty acid intermediates, metabolic state and nutrient availability to control mmpL gene expression and change its cell wall composition. If true, then defining the exquisite regulatory mechanisms that underlie the regulation of MmpL3 and MmpL11 transporters will generate novel insights into the transition between actively dividing Mtb and latent Mtb.

What projects are you currently working on and are there opportunities for fellow faculty to participate?

Current projects aim to 1) Characterize the function and regulation of MmpL transporters, 2) Define determinants of Mtb persistence, and 3) Translate insight on cell wall biogenesis and MmpL transporters into much-needed therapeutics for drug-susceptible and drug-resistant Mtb. Collaborations with analytical biochemists, structural biologists and medicinal chemists strengthen my research program; and combined, these approaches provide a unique perspective on Mtb physiology, virulence and putative drug targets.

A hypothetical: If you could have one tool that would solve a seemingly impenetrable problem in your work, what would it do? You have unlimited resources to design this tool, so think big.

Mtb infects one third of the world population, and most people are latently infected. TB treatment is lengthy with standard antibiotics, and there is a dire need for novel therapeutics to combat the phenotypically drug-resistant latent Mtb and emerging multi-drug resistant Mtb strains. My goal is to translate our findings on MmpL transporter function into compounds that impact multiple MmpL targets. This conceptually innovative approach would result in the development of a single molecule that could inhibit both MmpL11 and MmpL3, which are important for latency and virulence and for growth, respectively. I would love it if we could capitalize on our genetic and biochemical expertise and significantly impact global health through novel TB therapeutics.

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