New treatment for drug-resistant fungal infections

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Immunocompromised Individuals With Drug-resistant Fungal Infections Have New

Hope

02/18/2009

Even

the most drug-resistant fungi can be eradicated in multiple in vitro

and in vivo models using a lethal combination of an antifungal agent

and inhibition of the heat shock protein Hsp90, according to a new

study by Whitehead Institute and University of Toronto researchers. The

findings could enable development of novel antifungal therapies for

patients with compromised immune systems.

Immunocompromised

individuals--including HIV, chemotherapy, and organ transfer

patients--with resistant fungal infections suffer mortality rates

ranging from 50 to 90 percent.

" Being a pediatric oncologist, I

have seen many unfortunate patients die from resistant fungal

infections, " says Luke Whitesell, a scientist in the lab of Whitehead

Member Lindquist. " It's incredibly frustrating to see a child

with their cancer in remission being slowly eaten alive by a fungus

like Aspergillus, and there's nothing you can do about it. "

The

development of effective antifungal drugs is limited by humans' close

evolutionary relationship with fungi, and, in recent years, fungi's

ever-evolving resistance to existing drugs. Former Lindquist

postdoctoral researcher and lead author of this study, Leah Cowen,

explains: " The drugs just don't wipe out the infection. So you wind up

with a small population of fungi living in a host that is exposed to

the drug for a long time, which favors evolution of drug resistance. "

Previous

studies suggested that Hsp90, which is found in both fungi and humans,

plays a vital role in the evolution of drug resistance. In this most

recent study, which appears in the February 24 issue of the Proceedings

of the National Academy of Science (PNAS), Whitehead researchers tested

Hsp90 inhibitors in combination with common antifungal drugs in an

attempt to block the growth of Candida albicans and Aspergillus

fumigatus, two of the most prevalent and lethal species that cause

fungal infections in humans.

The researchers found that when

antifungals or Hsp90 inhibitors are used individually, they are

ineffective; however, when paired they form a deadly duo.

" When

you combine the two, you reduce Hsp90 function enough that the fungi

can no longer mount the crucial stress responses to antifungals

required for survival, " says Cowen. " So you cripple the fungus by

severely compromising its stress responses. "

According to

Lindquist, " This is an entirely new strategy for making fungi

susceptible to preexisting drugs and for preventing fungi from

deploying the resistance mechanisms, which they have evolved against

those compounds. It could make the difference between life and death. "

Because

Hsp90 is highly conserved, finding a compound to turn off Hsp90 in

fungi, but not in humans, is a significant hurdle scientists must

overcome. In addition, current Hsp90 inhibitors are toxic in mice with

resistant fungal infections. To find promising Hsp90 inhibitors for

antifungal therapy, Lindquist's lab has received a grant from the

Molecular Libraries Probe Center Network (MLPCN) Program of the

National Institutes of Health. The grant will allow researchers to

screen large numbers of compounds in the search for potential

fungus-selective Hsp90 inhibitors.

Still, even if the screen is successful, the battle between humans and fungi is

not over.

" Eventually,

like most drugs, Hsp90 inhibitors too, will become subject to

resistance, " suggests Lindquist, who is also a Medical

Institute investigator and professor of biology at MIT. " But in the

meantime, these inhibitors will open a very large window of opportunity

for individuals with resistant fungal infections. "

This research

was supported by Damon Runyon Cancer Research Foundation, a Genzyme

Fellowship, the Burroughs Wellcome Fund, the G. Harold and Leila Y.

Mathers Charitable Foundation, and a Canadian Institutes for Health

Research Grant.

Lindquist's primary affiliation is with

Whitehead Institute for Biomedical Research, where her laboratory is

located and all her research is conducted. She is also a

Medical Institute investigator and a professor of biology at

Massachusetts Institute of Technology.

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-resistant-Fungal-Infections-Have-New-Hope