Compromising fungi in the immunocompromised

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Public release date: 9-Feb-2009

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http://www.eurekalert.org/pub_releases/2009-02/wifb-thc020909.php

The Hsp90-Antifungal Combo, please: Compromising fungi in the

immunocompromised

IMAGE: The researchers found that when antifungals or Hsp90

inhibitors are used individually, they are ineffective; however, when

paired they form a deadly duo. Not only did this work in a...

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CAMBRIDGE, Mass. (February 9, 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.

Full Citation:

" Harnessing Hsp90 Function as a Powerful, Broadly Effective

Therapeutic Strategy for Fungal Infectious Disease "

PNAS, February 24, 2009

Leah E. Cowen (1), Sheena D. Singh (1), R. Köhler (2), Cahty

(1), Aimme K. Zaas (3), Wiley Schell (3), Hamza Aziz (3),

Eleftherios Mylonakis (4), R. Perfect (3,5), Luke Whitesell (6),

Lindquist (6)

1. Department of Molecular Genetics, University of Toronto, Toronto,

ON M5S 1A8, Canada.

2. Division of Infectious Disease, Children's Hospital, Boston, MA

02115, USA.

3. Department of Medicine, Duke University Medical Center, Durham, NC

27710, USA.

4. Harvard Medical School, Massachusetts General Hospital, Division

of Infectious Diseases, Boston, MA 02114, USA.

5. Department of Molecular Genetics and Microbiology, Duke University

Medical Center, Durham, NC 27710, USA.

6. Whitehead Institute for Biomedical Research, Medical

Institute, Massachusetts Institute of Technology, Cambridge, MA

02142, USA.