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publicado em 09/09/2011 às 16h21:00
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University of Toronto makes targeted therapy of fungal infections

This combination therapy away from common infections of medical devices, catheters and artificial joints

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Researchers at the University of Toronto have developed a therapy for a potentially deadly type of infection common in catheters, artificial joints and other medical devices "in housing."

Predicted therapy of fungal infections is difficult to treat for such devices because they are composed of biofilms - complex groups of cells that bind to the surfaces. Biofilms, in turn, are coated with a sticky matrix that is resistant to drugs.

Patients often undergo surgical removal of the infected catheter or other device in an attempt to clear the disease and prevent spread of infectious cells in the whole system.

In an article published in the journal PLoS Pathogens, the researchers showed that the inhibition of a protein called Hsp90 suppresses drug resistance in two major human fungal pathogens, Candida albicans and Aspergillus fumigatus. "You have to make the classic antifungals, which were not effective against biofilms, very effective," said Professor Leah Cowen, principal investigator on the study, which maintain the Canada Research Chair in Microbial Genomics and Infectious Disease at the U of T's Department of Molecular Genetics.

In an animal model of central venous catheters infected by a deadly fungus, the researchers were able to completely clear the infection by inhibiting Hsp90 and applying antifungal.

This approach worked with the most commonly prescribed class of antifungals, called azoles, and the only new class in the market, the echinocandins, a quick translation of a good prognosis for the treatment of the patient.

Moreover, the strategy worked with genetic or pharmacological inhibition of Hsp90. The researchers, including Nicole Robbins at U of T, a drug used to inhibit Hsp90, which is in Phase 2 clinical development for cancer and appears to be well tolerated by patients. Although researchers have discovered that the drug causes toxicity in preclinical experiments in the whole system of fungal infections in this study, the drug proved to be safe - probably because it remained localized at the infection site.

Blood flow around catheters and other devices for housing, creates a kind of lock that limits the spread of drugs and devices are typically open to the outside world, facilitating drug delivery. "This suggests that it might be possible to move very quickly towards a clinical therapy," said Cowen.

The researchers also showed that inhibition of Hsp90 blocks the ability of infected cells to disperse from biofilms. "When we inhibit Hsp90 alone without antifungals, the biofilm remains healthy, but the few cells that were not viable? Were dispersed. This is also an important clinical finding. You still do not want a large population of the fungus inside the body, but it would be nice to know that he's not going anywhere, "said Cowen.

Fungi 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. The number of bloodstream infections acquired by fungi, increased 200% over the past two decades, partly because the successful treatments for diseases previously fatal as cancer and AIDS have left many patients immuno-compromised and susceptible to infection.

With more than 10 million patients a year receive catheters, artificial joints and other devices, there is an urgent need for a better understanding of biofilms and their role in drug resistance of pathogenic fungi.

In 2005, Cowen and his team discovered the mechanism by which Hsp90 regulates drug resistance in non-biofilm, or free-floating situation. This study also extended this work and determined that the same mechanism - the stabilization of two downstream proteins that allow the yeast cells to withstand the stress of drug exposed - not in the action of fungal biofilms.

This discovery opened a new and important line of research on how drug-resistant biofilms. "When we reduce the levels of Hsp90, we see a reduction in one of the main components of the extracellular matrix around the biofilm, which blocks the action of the drug to stay inside. Hsp90 seems to regulate an important component of the matrix, called glucan, which is known to block access to drugs designed to kill fungal cells. It is a plausible mechanism, and something to be further explored, "said Cowen.

   Palavras-chave:   Infection    Fungi    Devices    Medical    Catheters    Artificial joints    Disease    Dispersal    Cells    Drugs    Toronto    Canada   
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