Hsp90 Potentiates the Rapid Evolution of New Traits: Drug Resistance in Diverse Fungi

Abstract

Hsp90 is a molecular chaperone for many signal transducers and may influence evolution by releasing previously silent genetic variation in response to environmental change. In fungi separated by approximately 800 million years of evolution, Hsp90 potentiated the evolution of drug resistance in a different way, by enabling new mutations to have immediate phenotypic consequences. Resistance was abrogated by Hsp90 inhibitors and by febrile temperatures, suggesting new therapeutic strategies and a clinical benefit of fever. During selection in a human host, drug resistance that was initially Hsp90-dependent evolved toward independence. Thus, Hsp90 can act in diverse ways to couple environmental contingency to the emergence and fixation of new traits.

Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence ofCandidaandAspergillusspecies

“…At concentrations well tolerated in humans, treatment with radicicol prevented the emergence of resistance to azoles and abrogated the resistance of laboratory mutants of C. albicans as well as C. albicans strains in which resistance to azoles developed in a human host. 99,100 More recently, 17-AAG and 17-DMAG administered at concentrations with minimal direct activity against C. albicans were synergistic in vitro with fluconazole. 101 The efficacy of fluconazole with these two Hsp90 inhibitors in an invertebrate model (larvae of the wax moth Galleria mellonella) was greater than that when it was administered alone as the combination therapy rescued larvae from lethal infection with C. albicans.…”

“…99,101 Inhibition of Hsp90 enhanced the activity of voriconazole against A. fumigatus, although this effect depended on environmental conditions. 101 Finally, combination treatment with geldanamycin and caspofungin rescued G. mellonella larvae from lethal infection with A. fumigatus.…”

“…1) in S. cerevisiae. 99 Similarly, investigators have shown that the Hsp90-calcineurin signaling network plays a key role in the rapid development and maintenance of C. albicans resistance to azoles as well as the echinocandins ( Table 1). At concentrations well tolerated in humans, treatment with radicicol prevented the emergence of resistance to azoles and abrogated the resistance of laboratory mutants of C. albicans as well as C. albicans strains in which resistance to azoles developed in a human host.…”

Analysis of genomic characters reveals that four distinct gene clusters are correlated with different functions in Burkholderia cenocepacia AU 1054

“…Furthermore, we searched the homology of these 826 genes against some functionally confirmed drug-resistance related genes at NCBI (www.ncbi.nlm.nih.gov), and we detected a substantial number of related genes (Supplementary Table S3), e.g., a gene for MFS_1 which belongs to the MFS that facilitates transport across cytoplasmic or internal membranes of a variety of substrates (Holden et al 2009); glnP, which encodes an ABC transporter permease protein that is associated with multidrug resistance (Moussatova et al 2008); emrB, which encodes a member of the drug resistance transporter EmrB/QacA subfamily (Ma et al 1994) and matE, which encodes a MATE efflux family protein that functions in MATE (Holden et al 2009). In responses to treatment with antimicrobial compounds, genes from drug resistance-related systems are under selection pressure in the long term (Cowen and Lindquist 2005;Sass et al 2011). Then a rapid evolution of virulence and drug resistance-related genes will emerge in the infectious pathogens (Cowen and Lindquist 2005).…”

“…In responses to treatment with antimicrobial compounds, genes from drug resistance-related systems are under selection pressure in the long term (Cowen and Lindquist 2005;Sass et al 2011). Then a rapid evolution of virulence and drug resistance-related genes will emerge in the infectious pathogens (Cowen and Lindquist 2005). Considering that rapid evolution is mainly due to the evolution of resistance genes (Hall 2004), the base usage bias at the second codon position could be reflected in drug resistance in B. cenocepacia.…”