Spotlight on the microbes that produce heat shock protein 90-targeting antibiotics

Peter W Piper,Stefan H Millson

doi:10.1098/rsob.120138

Abstract

Heat shock protein 90 (Hsp90) is a promising cancer drug target as a molecular chaperone critical for stabilization and activation of several of the oncoproteins that drive cancer progression. Its actions depend upon its essential ATPase, an activity fortuitously inhibited with a very high degree of selectivity by natural antibiotics: notably the actinomycete-derived benzoquinone ansamycins (e.g. geldanamycin) and certain fungal-derived resorcyclic acid lactones (e.g. radicicol). The molecular interactions made by these antibiotics when bound within the ADP/ATP-binding site of Hsp90 have served as templates for the development of several synthetic Hsp90 inhibitor drugs. Much attention now focuses on the clinical trials of these drugs. However, because microbes have evolved antibiotics to target Hsp90, it is probable that they often exploit Hsp90 inhibition when interacting with each other and with plants. Fungi known to produce Hsp90 inhibitors include mycoparasitic, as well as plant-pathogenic, endophytic and mycorrhizal species. The Hsp90 chaperone may, therefore, be a prominent target in establishing a number of mycoparasitic (interfungal), fungal pathogen–plant and symbiotic fungus–plant relationships. Furthermore the Hsp90 family proteins of the microbes that produce Hsp90 inhibitor antibiotics are able to reveal how drug resistance can arise by amino acid changes in the highly conserved ADP/ATP-binding site of Hsp90.

Highlights

Heat shock protein 90 (Hsp90) is essential for the conformational maturation, activation and maintenance of proteins needed for all of the six hallmarks of cancer: angiogenesis, immortalization, metastasis, impaired apoptosis, insensitivity to antigrowth signals and autocrine growth [1,2]
In this review, we focus solely on the benzoquinone ansamycins and the fungal-derived resorcyclic acid lactones (RALs), because these are the natural inhibitors where high-resolution crystal structures have revealed in atomic detail the interactions made as they bind within the Hsp90 N-terminal domain
The discovery of antibiotics highly selective for Hsp90, and the subsequent development of drugs based upon the molecular interactions made by these antibiotics within the ADP/ATP-binding site of Hsp90 are a classic example of this

Summary

Heat shock protein 90 (Hsp90) is a promising cancer drug target as a molecular chaperone critical for stabilization and activation of several of the oncoproteins that drive cancer progression. The molecular interactions made by these antibiotics when bound within the ADP/ATP-binding site of Hsp have served as templates for the development of several synthetic Hsp inhibitor drugs. Because microbes have evolved antibiotics to target Hsp, it is probable that they often exploit Hsp inhibition when interacting with each other and with plants. Fungi known to produce Hsp inhibitors include mycoparasitic, as well as plant-pathogenic, endophytic and mycorrhizal species. The Hsp chaperone may, be a prominent target in establishing a number of mycoparasitic (interfungal), fungal pathogen –plant and symbiotic fungus –plant relationships. The Hsp family proteins of the microbes that produce Hsp inhibitor antibiotics are able to reveal how drug resistance can arise by amino acid changes in the highly conserved ADP/ATP-binding site of Hsp

Introduction

The discovery of natural product inhibitors of heat shock protein 90

Why might fungi use heat shock protein 90 as an antibiotic target?

Findings

Conclusions