white_tedYour work focuses on drug resistance in Candida albicans. What are some of the drugs C. albicans can develop resistance to?

My research is focused on resistance to azole drugs; the number one azole is fluconazole, which is known as diflucan by patients. Essentially, when you get resistance to one azole drug, you get resistance to all azoles because of cross resistance. There are now about five or six azoles that are available by prescription, and some are broader spectrum than fluconazole. Then there is another class of azole drugs that you can get over-the-counter to treat your athlete’s foot and jock itch.

Is there more resistance in over-the-counter azoles?

Dermatophytes are the fungi that cause athlete’s foot, etc., and curiously, those fungi don’t show increased resistance, despite the over-the-counter azole drugs. In collaboration with the Broad Institute, I’ve facilitated sequencing of five dermatophyte genomes, and now we have the tools to ask questions about why these dermatophytes are not developing high levels of resistance despite over-the-counter azole use.

Is resistance a problem all over the world or are there localized problems?

The biggest problem with resistance to azole drugs was in the 1990s, with HIV patients. They were getting low doses of azoles for long periods of time as prophylaxis against fungal infections – perfect conditions to develop resistance. Near the end of the 90s, in London and other cities, as much as 33% of HIV patients had resistant Candida in their mouths. However, antiretroviral therapy has eliminated the need to treat these HIV patients with azole drugs for prophylaxis, and the frequency of resistance now is considerably lower. But what we are continuing to see is a shift from the susceptible species to resistant species. Two species called, C. glabrata and C. krusei, are increasing in frequency.

My major research focus is how fungal cells respond to azole drugs. And we learn a lot about how they respond from studying resistant isolates.

What are the mechanisms of resistance that they use?

If you think about drugs in a yeast cell, the drug has to get in, it has to interact with a target, and it can get pumped out. For the last 10 or 15 years we’ve understood that the target enzyme can be mutated in many different regions, so there’s no one specific point of mutation; the target enzyme can be mutated throughout the gene to create resistance. The target enzyme could also be over-expressed so you have more enzymes per cell so you need more drug per cell. Finally, there are two different classes of efflux pumps that pump the drugs out of the cell and these are over-expressed. Recently we’ve been analyzing how azoles are imported into the cell. We’ve shown that actually they don’t just diffuse in; there is clearly a facilitated diffusion.

Your work has shown that some isolates exhibit resistance that is inducible and transient. How does that work?

Sometimes cells have the ability to turn on pumps in response to drugs and then turn them off when the drug is removed. That might be an explanation for why the dermatophytes are not developing lots of true resistance, but that’s purely hypothesis right now.

Can some forms of resistance be swapped among different species?

In fungi there are no plasmids, like in bacteria, and we’ve never seen genetic exchange of resistance.

What’s been the most surprising thing in your research recently?

The import analysis has been the most interesting recent finding. That’s a whole mechanism that no one has yet appreciated about how these drugs interact with the cell, and we have to learn about how the drugs are actually getting into these cells.

If you had to change careers today and you could do anything, what would you do?

There’s always an interesting question in the fungi to answer. For the past 15 years or so I’ve really been fascinated by the fungi.

What is something about you that most people don’t know?

I’ve always worked on single celled eukaryotic organisms. I started on ciliated protozoans and spent the 1980s working on parasitic protozoans, and now I work on fungi.