By Jim Oldfield
Researchers at the University of Toronto have developed a therapy for a potentially deadly type of infection common in catheters, artificial joints and other “in-dwelling” medical devices.
The therapy targets fungal infections, which are hard to treat in such devices because they are composed of biofilms—complex groupings of cells that attach to surfaces. Biofilms, in turn, are coated in a gooey matrix that resists drugs.
Patients often undergo surgical removal of the infected catheter or other device in an attempt to clear the disease and prevent a system-wide dispersal of infecting cells.
In a paper published in the scientific journal PLoS Pathogens, the researchers showed that inhibiting the function of a protein called Hsp90 abolishes drug resistance in the two main human fungal pathogens, Candida albicans and Aspergillus fumigatus. “It takes classic antifungals, which were not effective against biofilms, and makes them very effective,” said Professor Leah Cowen, principal investigator on the study, who holds the Canada Research Chair in Microbial Genomics and Infectious Disease at U of T’s Department of Molecular Genetics.
In an animal model of a central venous catheter infected with deadly fungus, the researchers were able to completely clear the infection by inhibiting Hsp90 and applying antifungals.
That the approach worked with the most-prescribed class of antifungals, called the azoles, and with the only new class to reach the market in decades, the echinocandins, bodes well for its rapid translation to patient treatment.
Furthermore, the strategy worked with either genetic or pharmacologic inhibition of Hsp90. One drug the investigators, including U of T’s Nicole Robbins, used to inhibit Hsp90 is in Phase 2 clinical development for cancer, and appears to be well-tolerated by patients. Though the researchers previously found that the drug causes toxicity in preclinical experiments with system-wide fungal infections, in the current study, the drug proved safe—likely because it remained localized at the site of the infection.
Blood flow around catheters and other in-dwelling devices creates a kind of lock that limits drug dispersal, and the devices are typically open to the outside, facilitating drug delivery. “That suggests it could be possible to move toward a clinical therapy very quickly,” said Cowen.
The researchers also showed that inhibiting Hsp90 blocks the ability of infecting cells to disperse from biofilms. “When we inhibited Hsp90, alone with no antifungals, the biofilm stayed healthy but the few cells that dispersed were not viable. That’s also a clinically important finding. You still wouldn’t want a big population of the fungus sitting your body, but it would nice to know it isn’t going anywhere,” said Cowen.
Fungal pathogens are a major clinical problem. Candida albicans is the third-leading cause of intravascular catheter-related infections, and is fatal in about 30% of infections associated with devices. And the number of acquired fungal bloodstream infections has increased by more than 200% over the last two decades, partly because successful treatments for previously fatal diseases like cancer and AIDS have left many patients immune-compromised and susceptible to infection.
With more than 10 million patients per year now receiving catheters, artificial joints and other devices, there is a pressing need for a better understanding of biofilms and their role in drug resistance of fungal pathogens.
In 2005, Cowen and her team uncovered the mechanism through which Hsp90 regulates drug resistance in a non-biofilm, or free-floating state. The current study also extended that work and determined that the same mechanism—stabilization of two downstream proteins that allow fungal cells to withstand the stress of drug exposure—is not at play in fungal biofilms.
That finding has opened an important new line of investigation into how biofilms confer drug resistance. “When we reduce Hsp90 levels, we see a reduction in a major component of the extracellular matrix around the biofilms that blocks the drug from getting in. Hsp90 seems to be regulating a major component of that matrix called glucans, which are known to block drugs from accessing the fungal cells they are intended to kill. It’s a plausible mechanism, and something to explore further,” said Cowen.