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

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.

Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation

“…Its ATPase activity is regulated by interactions with a cochaperone such as cell division cycle 37 . The importance of this activity is suggested by the large number of natural antibiotics of fungal origin that selectively target this domain, and Hsp90 has been shown to interact with and to stabilize the majority of kinases in the human genome . Our data reveal that inhibition of the ATPase activity of Hsp90 using Rad results in the rapid ubiquitination and proteasomal degradation of c‐Src, and restores the normal kinetics of neutrophil apoptosis, both in circulating neutrophils from septic patients and in LPS‐stimulated neutrophils from healthy controls.…”

“…Its ATPase activity is regulated by interactions with a cochaperone such as cell division cycle 37. 37 The importance of this activity is suggested by the large number of natural antibiotics of fungal origin that selectively target this domain, 38 and…”

Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

“…Microbial natural products provide some of the most promising leads for abrogating antifungal drug resistance by crippling stress response pathways. For example, bacterial and fungal species produce diverse chemical scaffolds that inhibit Hsp90 41 . For soil-dwelling bacteria such as the Streptomycetes that produce Hsp90 inhibitors, this may provide them with an advantage in microbial communities by inhibiting growth of fungal competitors.…”

“…For soil-dwelling bacteria such as the Streptomycetes that produce Hsp90 inhibitors, this may provide them with an advantage in microbial communities by inhibiting growth of fungal competitors. Hsp90 inhibitors are also produced by diverse fungi, including mycopathogens, plant pathogens, and those with symbiotic relationships with plants 41 . For fungi, production of Hsp90 inhibitors to which they are resistant may be key for the establishment of parasitic or symbiotic relationships.…”

Heat Shock Protein 90 (Hsp90) as a Molecular Target for the Development of Novel Drugs Against the Dermatophyte Trichophyton rubrum

“…Inhibitors of Hsp90 have been thoroughly searched for and some natural compounds produced by microorganisms have been isolated. These include geldanamycin, which is a benzoquinone ansamycin derived from actinomycetes, and a resorcyclic acid lactone called radicicol produced by certain fungal species ( Piper and Millson, 2012 ). Some Hsp90 inhibitors are in clinical trial for cancer therapy and derivatives of natural compounds have been synthesized to increase efficacy and decrease side effects and toxicity ( Gorska et al, 2012 ).…”