Stress Protein Plays a Role in the Evolution of Drug Resistance in Fungi

Susan Lindquist, Ph.D.
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts
Pilot Project Funding from P30ES2109

Background: Heat shock proteins (HSPs), also called stress proteins, are a group of proteins that are present in all cells in all life forms. They are induced when a cell undergoes various types of environmental stresses like heat, cold and oxygen deprivation. HSPs are also present in cells under perfectly normal conditions. They act like chaperones, making sure that cellular proteins are in the right shape and in the right place at the right time. For example, HSPs help new or distorted proteins fold into shape, which is essential for proper function. They also shuttle proteins from one compartment to another inside the cell, and transport old proteins for disposal. HSPs are also believed to play a role in the presentation of peptides on the cell surface to help the immune system recognize diseased cells.

Recent research has suggested that a specific stress protein, known as HSP90, could be involved in the development of antibiotic resistance in yeast. With a small amount of funding as a pilot project from the Environmental Health Sciences Center at the Massachusetts Institute of Technology, these researchers performed studies to determine the capacity of HSP90 to influence the pace at which resistance would develop and the diversity of the types of resistance that arise.

Advance: Drug resistance was investigated in two classes of drugs; azoles, the most broadly used antifungal compounds, and echinocandins, the first new antifungal class in decades. HSP90 was found to enhance the evolution of drug resistance by enabling spontaneous mutations to have immediate phenotypic consequences. Drug resistance was attenuated by HSP inhibitors and by high temperatures.

Implications: These results represent an entirely new function of HSP90 in evolutionary processes. Fungal drug resistance is of great economic importance. There are only a few clinically useful drugs and resistance has emerged in all of them. Inhibiting HSP90 may render resistant fungal pathogens more vulnerable to anti-fungal treatments. HSP90 inhibitors are effective in overcoming fungal drug resistant at doses that are well tolerated.

Citation: Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science. 2005 Sep 30;309(5744):2185-9.