A Fungal Achilles' Heel

摘要

The emergence of drug resistance in pathogenic microbes provides a resounding validation of Darwinian evolution and yet forces a sobering realization that we share this planet with organisms whose long-term survival threatens our own. This threat is particularly poignant with eukaryotic pathogenic microbes whose cellular machinery is similar to that of our own cells, making drug target identification and development of antimicrobial agents all the more challenging. And with the development of drug resistance in pathogenic fungi and parasites—such as resistance to azole drugs that target ergosterol (a unique membrane sterol in fungi such as Candida albicans) synthesis, or resistance to chloroquine and mefloquine in the malaria parasite Plasmodium falciparum—we are often only one step ahead of disaster. The study by Cowen and Lindquist on page 2185 of this issue begins with a basic interest in molecular events that presage microbial drug resistance (/) and unveils a role for a heat shock protein called Hsp90 in enabling pathogenic fungi to rapidly develop drug resistance. Hsp90 is best known as a molecular chaperone that allows cells and organisms to cope with protein folding defects that arise from insults including mutations and environmental stress. Cowen and Lindquist show that Hsp90 enables the evolution of phenotypic diversity in fungi in response to evolutionarily selective forces. The work also implicates Hsp90 as an Achilles' heel of pathogenic fungi that could be harnessed by small-molecule ligands to improve and extend the armamentarium of antimicrobial agents.